Basic B cell function: bind to an antigen, receive help from a cognate helper T cell, and differentiate into a plasma cell that secretes large amounts of antibodies
3D rendering of a B cell
B cells, also known as B lymphocytes, are a type of white blood cell of the lymphocyte subtype. They function in the humoral immunity component of the adaptive immune system. B cells produce antibody
molecules; however, these antibodies are not secreted. Rather, they are
inserted into the plasma membrane where they serve as a part of B-cell receptors.
When a naïve or memory B cell is activated by an antigen, it
proliferates and differentiates into an antibody-secreting effector
cell, known as a plasmablast or plasma cell. Additionally, B cells present antigens (they are also classified as professional antigen-presenting cells (APCs)) and secrete cytokines.
In mammals, B cells mature in the bone marrow, which is at the core of most bones. In birds, B cells mature in the bursa of Fabricius, a lymphoid organ where they were first discovered by Chang and Glick, which is why the 'B' stands for bursa and not bone marrow as commonly believed.
Early B cell development: from stem cell to immature B cell
B cells undergo two types of selection while developing in the bone
marrow to ensure proper development, both involving B cell receptors
(BCR) on the surface of the cell. Positive selection occurs through
antigen-independent signaling involving both the pre-BCR and the BCR. If these receptors do not bind to their ligand, B cells do not receive the proper signals and cease to develop.
Negative selection occurs through the binding of self-antigen with the
BCR; If the BCR can bind strongly to self-antigen, then the B cell
undergoes one of four fates: clonal deletion, receptor editing, anergy, or ignorance (B cell ignores signal and continues development). This negative selection process leads to a state of central tolerance, in which the mature B cells do not bind self antigens present in the bone marrow.
To complete development, immature B cells migrate from the bone marrow into the spleen as transitional B cells, passing through two transitional stages: T1 and T2. Throughout their migration to the spleen and after spleen entry, they are considered T1 B cells. Within the spleen, T1 B cells transition to T2 B cells.
T2 B cells differentiate into either follicular (FO) B cells or
marginal zone (MZ) B cells depending on signals received through the BCR
and other receptors. Once differentiated, they are now considered mature B cells, or naive B cells.
Transitional B cell development: from immature B cell to MZ B cell or mature (FO) B cell
Activation
B cell activation: from immature B cell to plasma cell or memory B cell
B cell activation occurs in the secondary lymphoid organs (SLOs), such as the spleen and lymph nodes.[1]
After B cells mature in the bone marrow, they migrate through the blood
to SLOs, which receive a constant supply of antigen through circulating
lymph. At the SLO, B cell activation begins when the B cell binds to an antigen via its BCR.
Although the events taking place immediately after activation have yet
to be completely determined, it is believed that B cells are activated
in accordance with the kinetic segregation model,
initially determined in T lymphocytes. This model denotes that before
antigen stimulation, receptors diffuse through the membrane coming into
contact with Lck and CD45
in equal frequency, rendering a net equilibrium of phosphorylation and
non-phosphorylation. It is only when the cell comes in contact with an
antigen presenting cell that the larger CD45 is displaced due to the
close distance between the two membranes. This allows for net
phosphorylation of the BCR and the initiation of the signal transduction
pathway.
Of the three B cell subsets, FO B cells preferentially undergo T
cell-dependent activation while MZ B cells and B1 B cells preferentially
undergo T cell-independent activation.
B cell activation is enhanced through the activity of CD21, a surface receptor in complex with surface proteins CD19 and CD81 (all three are collectively known as the B cell coreceptor complex).
When a BCR binds an antigen tagged with a fragment of the C3 complement
protein, CD21 binds the C3 fragment, co-ligates with the bound BCR, and
signals are transduced through CD19 and CD81 to lower the activation
threshold of the cell.
T cell-dependent activation
Antigens that activate B cells with the help of T-cell are known as T cell-dependent (TD) antigens and include foreign proteins. They are named as such because they are unable to induce a humoral response in organisms that lack T cells.
B cell responses to these antigens takes multiple days, though
antibodies generated have a higher affinity and are more functionally
versatile than those generated from T cell-independent activation.
Once a BCR binds a TD antigen, the antigen is taken up into the B cell through receptor-mediated endocytosis, degraded, and presented to T cells as peptide pieces in complex with MHC-II molecules on the cell membrane. T helper (TH) cells, typically follicular T helper (TFH) cells recognize and bind these MHC-II-peptide complexes through their T cell receptor (TCR). Following TCR-MHC-II-peptide binding, T cells express the surface protein CD40L as well as cytokines such as IL-4 and IL-21. CD40L serves as a necessary co-stimulatory factor for B cell activation by binding the B cell surface receptor CD40, which promotes B cell proliferation, immunoglobulin class switching, and somatic hypermutation as well as sustains T cell growth and differentiation. T cell-derived cytokines bound by B cell cytokine receptors also promote B cell proliferation, immunoglobulin class switching, and somatic hypermutation as well as guide differentiation. After B cells receive these signals, they are considered activated.
T-dependent B cell activation
Once activated, B cells participate in a two-step differentiation
process that yields both short-lived plasmablasts for immediate
protection and long-lived plasma cells and memory B cells for persistent
protection. The first step, known as the extrafollicular response, occurs outside lymphoid follicles but still in the SLO.
During this step activated B cells proliferate, may undergo
immunoglobulin class switching, and differentiate into plasmablasts that
produce early, weak antibodies mostly of class IgM. The second step consists of activated B cells entering a lymphoid follicle and forming a germinal center (GC), which is a specialized microenvironment where B cells undergo extensive proliferation, immunoglobulin class switching, and affinity maturation directed by somatic hypermutation. These processes are facilitated by TFH cells within the GC and generate both high-affinity memory B cells and long-lived plasma cells.
Resultant plasma cells secrete large amounts of antibody and either
stay within the SLO or, more preferentially, migrate to bone marrow.
Antigens that activate B cells without T cell help are known as T cell-independent (TI) antigens and include foreign polysaccharides and unmethylated CpG DNA. They are named as such because they are able to induce a humoral response in organisms that lack T cells.
B cell response to these antigens is rapid, though antibodies generated
tend to have lower affinity and are less functionally versatile than
those generated from T cell-dependent activation.
As with TD antigens, B cells activated by TI antigens need
additional signals to complete activation, but instead of receiving them
from T cells, they are provided either by recognition and binding of a
common microbial constituent to toll-like receptors (TLRs) or by extensive crosslinking of BCRs to repeated epitopes on a bacterial cell.
B cells activated by TI antigens go on to proliferate outside lymphoid
follicles but still in SLOs (GCs do not form), possibly undergo
immunoglobulin class switching, and differentiate into short-lived
plasmablasts that produce early, weak antibodies mostly of class IgM,
but also some populations of long-lived plasma cells.
Memory B cell activation
Memory B cell activation begins with the detection and binding of their target antigen, which is shared by their parent B cell.
Some memory B cells can be activated without T cell help, such as
certain virus-specific memory B cells, but others need T cell help.
Upon antigen binding, the memory B cell takes up the antigen through
receptor-mediated endocytosis, degrades it, and presents it to T cells
as peptide pieces in complex with MHC-II molecules on the cell membrane. Memory T helper (TH) cells, typically memory follicular T helper (TFH)
cells, that were derived from T cells activated with the same antigen
recognize and bind these MHC-II-peptide complexes through their TCR. Following TCR-MHC-II-peptide binding and the relay of other signals from the memory TFH
cell, the memory B cell is activated and differentiates either into
plasmablasts and plasma cells via an extrafollicular response or enter a
germinal center reaction where they generate plasma cells and more
memory B cells. It is unclear whether the memory B cells undergo further affinity maturation within these secondary GCs.
B cell types
Plasmablast – A short-lived, proliferating antibody-secreting cell arising from B cell differentiation.
Plasmablasts are generated early in an infection and their antibodies
tend to have a weaker affinity towards their target antigen compared to
plasma cell.
Plasmablasts can result from T cell-independent activation of B cells
or the extrafollicular response from T cell-dependent activation of B
cells.
Plasma cell – A long-lived, non-proliferating antibody-secreting cell arising from B cell differentiation. There is evidence that B cells first differentiate into a plasmablast-like cell, then differentiate into a plasma cell.
Plasma cells are generated later in an infection and, compared to
plasmablasts, have antibodies with a higher affinity towards their
target antigen due to affinity maturation in the germinal center (GC)
and produce more antibodies.
Plasma cells typically result from the germinal center reaction from T
cell-dependent activation of B cells, however they can also result from T
cell-independent activation of B cells.
Memory B cell – Dormant B cell arising from B cell differentiation.
Their function is to circulate through the body and initiate a
stronger, more rapid antibody response (known as the anamnestic
secondary antibody response) if they detect the antigen that had
activated their parent B cell (memory B cells and their parent B cells
share the same BCR, thus they detect the same antigen).
Memory B cells can be generated from T cell-dependent activation
through both the extrafollicular response and the germinal center
reaction as well as from T cell-independent activation of B1 cells.
B-2 cell – FO B cells and MZ B cells.
Follicular (FO) B Cell
(also known as a B-2 cell) – Most common type of B cell and, when not
circulating through the blood, is found mainly in the lymphoid follicles
of secondary lymphoid organs (SLOs). They are responsible for generating the majority of high-affinity antibodies during an infection.
Marginal zone (MZ) B cell
– Found mainly in the marginal zone of the spleen and serves as a first
line of defense against blood-borne pathogens, as the marginal zone
receives large amounts of blood from the general circulation.
They can undergo both T cell-independent and T cell-dependent
activation, but preferentially undergo T cell-independent activation.
B-1 cell – Arises from a developmental pathway different from FO B cells and MZ B cells. In mice, they predominantly populate the peritoneal cavity and pleural cavity, generate natural antibodies (antibodies produced without infection), defend against mucosal pathogens, and primarily exhibit T cell-independent activation.
A true homologue of mouse B-1 cells has not been discovered in humans,
though various cell populations similar to B-1 cells have been
described.
Regulatory B (Breg) cell – An immunosuppressive
B cell type that stops the expansion of pathogenic, pro-inflammatory
lymphocytes through the secretion of IL-10, IL-35, and TGF-β. Also, it promotes the generation of regulatory T (Treg) cells by directly interacting with T cells to skew their differentiation towards Tregs.
No common Breg cell identity has been described and many Breg cell
subsets sharing regulatory functions have been found in both mice and
humans.
It is currently unknown if Breg cell subsets are developmentally linked
and how exactly differentiation into a Breg cell occurs.
There is evidence showing that nearly all B cell types can
differentiate into a Breg cell through mechanisms involving inflammatory
signals and BCR recognition.
A study that investigated the methylome of B cells along their differentiation cycle, using whole-genome bisulfite sequencing
(WGBS), showed that there is a hypomethylation from the earliest stages
to the most differentiated stages. The largest methylation difference
is between the stages of germinal center B cells and memory B cells.
Furthermore, this study showed that there is a similarity between B cell
tumors and long-lived B cells in their DNA methylation signatures.
T cells are born from hematopoietic stem cells, found in the bone marrow. Developing T cells then migrate to the thymus gland to mature. T cells derive their name from this organ where they develop (or mature).
After migration to the thymus, the precursor cells mature into several
distinct types of T cells. T cell differentiation also continues after
they have left the thymus. Groups of specific, differentiated T cell
subtypes have a variety of important functions in controlling and
shaping the immune response.
One of these functions is immune-mediated cell death,
and it is carried out by two major subtypes: CD8+ "killer" and CD4+
"helper" T cells. (These are named for the presence of the cell surface
proteins CD8 or CD4.) CD8+ T cells, also known as "killer T cells", are cytotoxic
– this means that they are able to directly kill virus-infected cells,
as well as cancer cells. CD8+ T cells are also able to use small
signaling proteins, known as cytokines, to recruit other types of cells when mounting an immune response. A different population of T cells, the CD4+
T cells, function as "helper cells". Unlike CD8+ killer T cells, these
CD4+ helper T cells function by indirectly killing cells identified as
foreign: they determine if and how other parts of the immune system
respond to a specific, perceived threat. Helper T cells also use cytokine signaling to influence regulatory B cells directly, and other cell populations indirectly.
Regulatory T cells are yet another distinct population of T cells that provide the critical mechanism of tolerance,
whereby immune cells are able to distinguish invading cells from
"self". This prevents immune cells from inappropriately reacting against
one's own cells, known as an "autoimmune"
response. For this reason, these regulatory T cells have also been
called "suppressor" T cells. These same regulatory T cells can also be
co-opted by cancer cells to prevent the recognition of, and an immune
response against, tumor cells.
Development
Origin, early development and migration to the thymus
All T cells originate from c-kit+Sca1+haematopoietic stem cells (HSC) which reside in the bone marrow. In some cases, the origin might be the fetal liver
during embryonic development. The HSC then differentiate into
multipotent progenitors (MPP) which retain the potential to become both
myeloid and lymphoid cells. The process of differentiation then proceeds
to a common lymphoid progenitor (CLP), which can only differentiate
into T, B or NK cells.
These CLP cells then migrate via the blood to the thymus, where they
engraft. The earliest cells which arrived in the thymus are termed
double-negative, as they express neither the CD4 nor CD8 co-receptor. The newly arrived CLP cells are CD4−CD8−CD44+CD25−ckit+ cells, and are termed early thymic progenitor (ETP) cells. These cells will then undergo a round of division and downregulate c-kit and are termed DN1 cells.
TCR development
A
critical step in T cell maturation is making a functional T cell
receptor (TCR). Each mature T cell will ultimately contain a unique TCR
that reacts to a random pattern, allowing the immune system to recognize
many different types of pathogens.
The TCR consists of two major components, the alpha and beta
chains. These both contain random elements designed to produce a wide
variety of different TCRs, but also therefore must be tested to make
sure they work at all. First, T cells attempt to create a functional
beta chain, testing it against a mock alpha chain. Then they attempt to
create a functional alpha chain. Once a working TCR has been produced, T
cells then must show their TCR can recognize the body’s MHC complex
(positive selection) and that it does not react to self proteins
(negative selection).
TCR-Beta selection
At the DN2 stage (CD44+CD25+), cells upregulate the recombination genes RAG1 and RAG2 and re-arrange the TCRβ locus, combining V-D-J
and constant region genes in an attempt to create a functional TCRβ
chain. As the developing thymocyte progresses through to the DN3 stage
(CD44−CD25+), the T cell expresses an invariant
α-chain called pre-Tα alongside the TCRβ gene. If the rearranged β-chain
successfully pairs with the invariant α-chain, signals are produced
which cease rearrangement of the β-chain (and silences the alternate
allele).
Although these signals require this pre-TCR at the cell surface, they
are independent of ligand binding to the pre-TCR. If the pre-TCR forms,
then the cell downregulates CD25 and is termed a DN4 cell (CD25−CD44−). These cells then undergo a round of proliferation and begin to re-arrange the TCRα locus.
Positive selection
Double-positive thymocytes (CD4+/CD8+) migrate deep into the thymic cortex, where they are presented with self-antigens. These self-antigens are expressed by thymic cortical epithelial cells on MHC
molecules on the surface of cortical epithelial cells. Only those
thymocytes that interact with MHC-I or MHC-II will receive a vital
"survival signal". All that cannot (if they do not interact strongly
enough) will die by "death by neglect" (no survival signal). This
process ensures that the selected T cells will have an MHC affinity that
can serve useful functions in the body (i.e., the cells must be able to
interact with MHC and peptide complexes to affect immune responses).
The vast majority of developing thymocytes will die during this process.
The process of positive selection takes a number of days.
A thymocyte's fate is determined during positive selection. Double-positive cells (CD4+/CD8+) that interact well with MHC class II molecules will eventually become CD4+ cells, whereas thymocytes that interact well with MHC class I molecules mature into CD8+ cells. A T cell becomes a CD4+
cell by down-regulating expression of its CD8 cell surface receptors.
If the cell does not lose its signal, it will continue downregulating
CD8 and become a CD4+, single positive cell.
This process does not remove thymocytes that may cause autoimmunity.
The potentially autoimmune cells are removed by the process of negative
selection, which occurs in the thymic medulla (discussed below).
Negative selection
Negative
selection removes thymocytes that are capable of strongly binding with
"self" MHC peptides. Thymocytes that survive positive selection migrate
towards the boundary of the cortex and medulla in the thymus. While in
the medulla, they are again presented with a self-antigen presented on
the MHC complex of medullary thymic epithelial cells (mTECs). mTECs must be AIRE+
to properly express self-antigens from all tissues of the body on their
MHC class I peptides. Some mTECs are phagocytosed by thymic dendritic
cells; this allows for presentation of self-antigens on MHC class II
molecules (positively selected CD4+ cells must interact with MHC class II molecules, thus APCs, which possess MHC class II, must be present for CD4+ T-cell negative selection). Thymocytes that interact too strongly with the self-antigen receive an apoptotic signal that leads to cell death. However, some of these cells are selected to become Treg cells. The remaining cells exit the thymus as mature naive T cells, also known as recent thymic emigrants. This process is an important component of central tolerance and serves to prevent the formation of self-reactive T cells that are capable of inducing autoimmune diseases in the host.
β-selection is the first checkpoint, where the T cells that are
able to form a functional pre-TCR with an invariant alpha chain and a
functional beta chain are allowed to continue development in the thymus.
Next, positive selection checks that T cells have successfully
rearranged their TCRα locus and are capable of recognizing peptide-MHC
complexes with appropriate affinity. Negative selection in the medulla
then obliterates T cells that bind too strongly to self-antigens
expressed on MHC molecules. These selection processes allow for
tolerance of self by the immune system. Typical T cells that leave the
thymus (via the corticomedullary junction) are self-restricted,
self-tolerant, and single positive.
Thymic output
About
98% of thymocytes die during the development processes in the thymus by
failing either positive selection or negative selection, whereas the
other 2% survive and leave the thymus to become mature immunocompetent T
cells.
The thymus contributes fewer cells as a person ages. As the thymus shrinks by about 3% a year throughout middle age, a corresponding fall in the thymic production of naive T cells occurs, leaving peripheral T cell expansion and regeneration to play a greater role in protecting older people.
Types of T cell
T
cells are grouped into a series of subsets based on their function. CD4
and CD8 T cells are selected in the thymus, but undergo further
differentiation in the periphery to specialized cells which have
different functions. T cell subsets were initially defined by function,
but also have associated gene or protein expression patterns.
Depiction of the various key subsets of CD4-positive T cells with corresponding associated cytokines and transcription factors.
T helper cells (TH cells) assist other lymphocytes, including maturation of B cells into plasma cells and memory B cells, and activation of cytotoxic T cells and macrophages. These cells are also known as CD4+ T cells as they express the CD4 glycoprotein on their surfaces. Helper T cells become activated when they are presented with peptideantigens by MHC class II molecules, which are expressed on the surface of antigen-presenting cells (APCs). Once activated, they divide rapidly and secrete cytokines
that regulate or assist the immune response. These cells can
differentiate into one of several subtypes, which have different roles.
Cytokines direct T cells into particular subtypes.
Superresolution image of a group of cytotoxic T cells surrounding a cancer cell
Cytotoxic T cells (TC cells, CTLs, T-killer cells, killer T cells) destroy virus-infected cells and tumor cells, and are also implicated in transplant rejection. These cells are defined by the expression of the CD8 protein on their cell surface. Cytotoxic T cells recognize their targets by binding to short peptides (8-11 amino acids in length) associated with MHC class I
molecules, present on the surface of all nucleated cells. Cytotoxic T
cells also produce the key cytokines IL-2 and IFNγ. These cytokines
influence the effector functions of other cells, in particular
macrophages and NK cells.
Antigen-naive T cells expand and differentiate into memory and effector T cells
after they encounter their cognate antigen within the context of an MHC
molecule on the surface of a professional antigen presenting cell (e.g.
a dendritic cell). Appropriate co-stimulation must be present at the
time of antigen encounter for this process to occur. Historically,
memory T cells were thought to belong to either the effector or central
memory subtypes, each with their own distinguishing set of cell surface
markers (see below).
Subsequently, numerous new populations of memory T cells were
discovered including tissue-resident memory T (Trm) cells, stem memory
TSCM cells, and virtual memory T cells. The single unifying theme for
all memory T cell
subtypes is that they are long-lived and can quickly expand to large
numbers of effector T cells upon re-exposure to their cognate antigen.
By this mechanism they provide the immune system with "memory" against
previously encountered pathogens. Memory T cells may be either CD4+ or CD8+ and usually express CD45RO.
Memory T cell subtypes:
Central memory T cells (TCM cells) express CD45RO, C-C chemokine receptor type 7 (CCR7), and L-selectin (CD62L). Central memory T cells also have intermediate to high expression of CD44. This memory subpopulation is commonly found in the lymph nodes and in the peripheral circulation. (Note- CD44 expression is usually used to distinguish murine naive from memory T cells).
Effector memory T cells (TEM cells and TEMRA cells) express CD45RO but lack expression of CCR7 and L-selectin. They also have intermediate to high expression of CD44. These memory T cells lack lymph node-homing receptors and are thus found in the peripheral circulation and tissues. TEMRA
stands for terminally differentiated effector memory cells
re-expressing CD45RA, which is a marker usually found on naive T cells.
Tissue resident memory T cells (TRM) occupy tissues (skin, lung, etc.) without recirculating. One cell surface marker that has been associated with TRM is the intern αeβ7, also known as CD103.
Virtual memory T cells differ from the other memory subsets in that
they do not originate following a strong clonal expansion event. Thus,
although this population as a whole is abundant within the peripheral
circulation, individual virtual memory T cell clones reside at
relatively low frequencies. One theory is that homeostatic proliferation
gives rise to this T cell population. Although CD8 virtual memory T
cells were the first to be described, it is now known that CD4 virtual memory cells also exist.
Regulatory T cells are crucial for the maintenance of immunological tolerance. Their major role is to shut down T cell-mediated immunity toward the end of an immune reaction and to suppress autoreactive T cells that escaped the process of negative selection in the thymus.
Two major classes of CD4+ Treg cells have been described — FOXP3+ Treg cells and FOXP3− Treg cells.
Regulatory T cells can develop either during normal development
in the thymus, and are then known as thymic Treg cells, or can be
induced peripherally and are called peripherally derived Treg cells.
These two subsets were previously called "naturally occurring" and
"adaptive" (or "induced"), respectively. Both subsets require the expression of the transcription factorFOXP3 which can be used to identify the cells. Mutations of the FOXP3 gene can prevent regulatory T cell development, causing the fatal autoimmune diseaseIPEX.
Several other types of T cells have suppressive activity, but do not express FOXP3 constitutively. These include Tr1 and Th3
cells, which are thought to originate during an immune response and act
by producing suppressive molecules. Tr1 cells are associated with
IL-10, and Th3 cells are associated with TGF-beta. Recently, Treg17 cells have been added to this list.
Innate-like T cells
Innate-like
T cells or unconventional T cells represent some subsets of T cells
that behave differently in immunity. They trigger rapid immune
responses, regardless of the major histocompatibility complex (MHC)
expression, unlike their conventional counterparts (CD4 T helper cells
and CD8 cytotoxic T cells), which are dependent on the recognition of
peptide antigens in the context of the MHC molecule. Overall, there are
three large populations of unconventional T cells: NKT cells, MAIT
cells, and gammadelta T cells. Now, their functional roles are already
being well established in the context of infections and cancer. Furthermore, these T cell subsets are being translated into many therapies against malignancies such as leukemia, for example.
Natural killer T cells (NKT cells – not to be confused with natural killer cells of the innate immune system) bridge the adaptive immune system with the innate immune system. Unlike conventional T cells that recognize protein peptide antigens presented by major histocompatibility complex (MHC) molecules, NKT cells recognize glycolipid antigens presented by CD1d.
Once activated, these cells can perform functions ascribed to both
helper and cytotoxic T cells: cytokine production and release of
cytolytic/cell killing molecules. They are also able to recognize and
eliminate some tumor cells and cells infected with herpes viruses.
Mucosal associated invariant T (MAIT) cells display innate, effector-like qualities.[24][25] In humans, MAIT cells are found in the blood, liver, lungs, and mucosa, defending against microbial activity and infection. The MHC class I-like protein, MR1, is responsible for presenting bacterially-produced vitamin B metabolites to MAIT cells. After the presentation of foreign antigen by MR1, MAIT cells secrete pro-inflammatory cytokines and are capable of lysing bacterially-infected cells. MAIT cells can also be activated through MR1-independent signaling. In addition to possessing innate-like functions, this T cell subset supports the adaptive immune response and has a memory-like phenotype. Furthermore, MAIT cells are thought to play a role in autoimmune diseases, such as multiple sclerosis, arthritis and inflammatory bowel disease, although definitive evidence is yet to be published.
Gamma delta T cells
(γδ T cells) represent a small subset of T cells which possess a γδ TCR
rather than the αβ TCR on the cell surface. The majority of T cells
express αβ TCR chains. This group of T cells is much less common in
humans and mice (about 2% of total T cells) and are found mostly in the
gut mucosa, within a population of intraepithelial lymphocytes.
In rabbits, sheep, and chickens, the number of γδ T cells can be as
high as 60% of total T cells. The antigenic molecules that activate γδ T
cells are still mostly unknown. However, γδ T cells are not
MHC-restricted and seem to be able to recognize whole proteins rather
than requiring peptides to be presented by MHC molecules on APCs. Some murine
γδ T cells recognize MHC class IB molecules. Human γδ T cells which use
the Vγ9 and Vδ2 gene fragments constitute the major γδ T cell
population in peripheral blood, and are unique in that they specifically
and rapidly respond to a set of nonpeptidic phosphorylated isoprenoid precursors, collectively named phosphoantigens,
which are produced by virtually all living cells. The most common
phosphoantigens from animal and human cells (including cancer cells) are
isopentenyl pyrophosphate (IPP) and its isomer dimethylallyl pyrophosphate (DMPP). Many microbes produce the highly active compound hydroxy-DMAPP (HMB-PP)
and corresponding mononucleotide conjugates, in addition to IPP and
DMAPP. Plant cells produce both types of phosphoantigens. Drugs
activating human Vγ9/Vδ2 T cells comprise synthetic phosphoantigens and aminobisphosphonates, which upregulate endogenous IPP/DMAPP.
The
T lymphocyte activation pathway: T cells contribute to immune defenses
in two major ways; some direct and regulate immune responses; others
directly attack infected or cancerous cells.
Activation of CD4+ T cells occurs through the simultaneous engagement of the T-cell receptor and a co-stimulatory molecule (like CD28, or ICOS) on the T cell by the major histocompatibility complex (MHCII) peptide and co-stimulatory molecules on the APC. Both are required for production of an effective immune response; in the absence of co-stimulation, T cell receptor signalling alone results in anergy. The signalling pathways downstream from co-stimulatory molecules usually engages the PI3K pathway generating PIP3 at the plasma membrane and recruiting PH domain containing signaling molecules like PDK1 that are essential for the activation of PKC-θ, and eventual IL-2 production. Optimal CD8+ T cell response relies on CD4+ signalling. CD4+ cells are useful in the initial antigenic activation of naive CD8 T cells, and sustaining memory CD8+ T cells in the aftermath of an acute infection. Therefore, activation of CD4+ T cells can be beneficial to the action of CD8+ T cells.
The first signal is provided by binding of the T cell receptor to
its cognate peptide presented on MHCII on an APC. MHCII is restricted
to so-called professional antigen-presenting cells, like dendritic cells, B cells, and macrophages, to name a few. The peptides presented to CD8+ T cells by MHC class I molecules are 8–13 amino acids in length; the peptides presented to CD4+ cells by MHC class II molecules are longer, usually 12–25 amino acids in length, as the ends of the binding cleft of the MHC class II molecule are open.
The second signal comes from co-stimulation, in which surface
receptors on the APC are induced by a relatively small number of
stimuli, usually products of pathogens, but sometimes breakdown products
of cells, such as necrotic-bodies or heat shock proteins.
The only co-stimulatory receptor expressed constitutively by naive T
cells is CD28, so co-stimulation for these cells comes from the CD80 and CD86 proteins, which together constitute the B7 protein, (B7.1 and B7.2, respectively) on the APC. Other receptors are expressed upon activation of the T cell, such as OX40
and ICOS, but these largely depend upon CD28 for their expression. The
second signal licenses the T cell to respond to an antigen. Without it,
the T cell becomes anergic,
and it becomes more difficult for it to activate in future. This
mechanism prevents inappropriate responses to self, as self-peptides
will not usually be presented with suitable co-stimulation. Once a T
cell has been appropriately activated (i.e. has received signal one and
signal two) it alters its cell surface expression of a variety of
proteins. Markers of T cell activation include CD69, CD71 and CD25 (also
a marker for Treg cells), and HLA-DR (a marker of human T cell
activation). CTLA-4 expression is also up-regulated on activated T
cells, which in turn outcompetes CD28 for binding to the B7 proteins.
This is a checkpoint mechanism to prevent over activation of the T cell.
Activated T cells also change their cell surface glycosylation profile.
The T cell receptor
exists as a complex of several proteins. The actual T cell receptor is
composed of two separate peptide chains, which are produced from the
independent T cell receptor alpha and beta (TCRα and TCRβ) genes. The other proteins in the complex are the CD3 proteins: CD3εγ and CD3εδ heterodimers and, most important, a CD3ζ homodimer, which has a total of six ITAM motifs. The ITAM motifs on the CD3ζ can be phosphorylated by Lck and in turn recruit ZAP-70. Lck and/or ZAP-70 can also phosphorylate the tyrosines on many other molecules, not least CD28, LAT and SLP-76, which allows the aggregation of signalling complexes around these proteins.
Phosphorylated LAT recruits SLP-76 to the membrane, where it can then bring in PLC-γ, VAV1, Itk and potentially PI3K. PLC-γ cleaves PI(4,5)P2 on the inner leaflet of the membrane to create the active intermediaries diacylglycerol (DAG), inositol-1,4,5-trisphosphate (IP3);
PI3K also acts on PIP2, phosphorylating it to produce
phosphatidlyinositol-3,4,5-trisphosphate (PIP3). DAG binds and activates
some PKCs. Most important in T cells is PKC-θ, critical for activating
the transcription factors NF-κB and AP-1. IP3 is released from the membrane by PLC-γ and diffuses rapidly to activate calcium channel receptors on the ER, which induces the release of calcium
into the cytosol. Low calcium in the endoplasmic reticulum causes STIM1
clustering on the ER membrane and leads to activation of cell membrane
CRAC channels that allows additional calcium to flow into the cytosol
from the extracellular space. This aggregated cytosolic calcium binds
calmodulin, which can then activate calcineurin. Calcineurin, in turn, activates NFAT, which then translocates to the nucleus. NFAT is a transcription factor
that activates the transcription of a pleiotropic set of genes, most
notable, IL-2, a cytokine that promotes long-term proliferation of
activated T cells.
PLC-γ can also initiate the NF-κB pathway.
DAG activates PKC-θ, which then phosphorylates CARMA1, causing it to
unfold and function as a scaffold. The cytosolic domains bind an adapter
BCL10 via CARD (Caspase activation and recruitment domains) domains; that then binds TRAF6, which is ubiquitinated at K63.
This form of ubiquitination does not lead to degradation of target
proteins. Rather, it serves to recruit NEMO, IKKα and -β, and TAB1-2/
TAK1.
TAK 1 phosphorylates IKK-β, which then phosphorylates IκB allowing for
K48 ubiquitination: leads to proteasomal degradation. Rel A and p50 can
then enter the nucleus and bind the NF-κB response element. This coupled
with NFAT signaling allows for complete activation of the IL-2 gene.
While in most cases activation is dependent on TCR recognition of
antigen, alternative pathways for activation have been described. For
example, cytotoxic T cells have been shown to become activated when
targeted by other CD8 T cells leading to tolerization of the latter.
A
unique feature of T cells is their ability to discriminate between
healthy and abnormal (e.g. infected or cancerous) cells in the body. Healthy cells typically express a large number of self derived pMHC
on their cell surface and although the T cell antigen receptor can
interact with at least a subset of these self pMHC, the T cell generally
ignores these healthy cells. However, when these very same cells
contain even minute quantities of pathogen derived pMHC, T cells are
able to become activated and initiate immune responses. The ability of T
cells to ignore healthy cells but respond when these same cells contain
pathogen (or cancer) derived pMHC is known as antigen discrimination.
The molecular mechanisms that underlie this process are controversial.
T
cell exhaustion is a state of dysfunctional T cells. It is
characterized by progressive loss of function, changes in
transcriptional profiles and sustained expression of inhibitory
receptors. At first cells lose their ability to produce IL-2 and TNFα
followed by the loss of high proliferative capacity and cytotoxic
potential, eventually leading to their deletion. Exhausted T cells
typically indicate higher levels of CD43, CD69 and inhibitory receptors combined with lower expression of CD62L and CD127. Exhaustion can develop during chronic infections, sepsis and cancer. Exhausted T cells preserve their functional exhaustion even after repeated antigen exposure.
During chronic infection and sepsis
T cell exhaustion can be triggered by several factors like persistent antigen exposure and lack of CD4 T cell help.
Antigen exposure also has effect on the course of exhaustion because
longer exposure time and higher viral load increases the severity of T
cell exhaustion. At least 2–4 weeks exposure is needed to establish
exhaustion. Another factor able to induce exhaustion are inhibitory receptors including programmed cell death protein 1 (PD1), CTLA-4, T cell membrane protein-3 (TIM3), and lymphocyte activation gene 3 protein (LAG3). Soluble molecules such as cytokines IL-10 or TGF-β are also able to trigger exhaustion. Last known factors that can play a role in T cell exhaustion are regulatory cells. Treg cells can be a source of IL-10 and TGF-β and therefore they can play a role in T cell exhaustion. Furthermore, T cell exhaustion is reverted after depletion of Treg cells and blockade of PD1.
T cell exhaustion can also occur during sepsis as a result of cytokine
storm. Later after the initial septic encounter anti-inflammatory
cytokines and pro-apoptotic proteins take over to protect the body from
damage. Sepsis also carries high antigen load and inflammation. In this
stage of sepsis T cell exhaustion increases. Currently there are studies aiming to utilize inhibitory receptor blockades in treatment of sepsis.
During transplantation
While
during infection T cell exhaustion can develop following persistent
antigen exposure after graft transplant similar situation arises with
alloantigen presence. It was shown that T cell response diminishes over time after kidney transplant.
These data suggest T cell exhaustion plays an important role in
tolerance of a graft mainly by depletion of alloreactive CD8 T cells.
Several studies showed positive effect of chronic infection on graft
acceptance and its long-term survival mediated partly by T cell
exhaustion. It was also shown that recipient T cell exhaustion provides sufficient conditions for NK cell transfer.
While there are data showing that induction of T cell exhaustion can be
beneficial for transplantation it also carries disadvantages among
which can be counted increased number of infections and the risk of
tumor development.
During cancer T cell exhaustion plays a role in tumor protection.
According to research some cancer-associated cells as well as tumor
cells themselves can actively induce T cell exhaustion at the site of
tumor. T cell exhaustion can also play a role in cancer relapses as was shown on leukemia.
Some studies have suggested that it is possible to predict relapse of
leukemia based on expression of inhibitory receptors PD-1 and TIM-3 by T
cells.
Many experiments and clinical trials have focused on immune checkpoint
blockers in cancer therapy, with some of these approved as valid
therapies that are now in clinical use.
Inhibitory receptors targeted by those medical procedures are vital in T
cell exhaustion and blocking them can reverse these changes.
Figure of the heavenly bodies — An illustration of the Ptolemaic geocentric system by Portuguese cosmographer and cartographer Bartolomeu Velho, 1568 (Bibliothèque Nationale, Paris)
In astronomy, the geocentric model (also known as geocentrism, often exemplified specifically by the Ptolemaic system) is a superseded description of the Universe with Earth at the center. Under the geocentric model, the Sun, Moon, stars, and planets all orbit Earth. The geocentric model was the predominant description of the cosmos in many ancient civilizations, such as those of Aristotle in Classical Greece and Ptolemy in Roman Egypt.
Two observations supported the idea that Earth was the center of the Universe:
First, from anywhere on Earth, the Sun appears to revolve around Earth once per day.
While the Moon and the planets have their own motions, they also appear
to revolve around Earth about once per day. The stars appeared to be fixed on a celestial sphere rotating once each day about an axis through the geographic poles of Earth.
Second, Earth seems to be unmoving from the perspective of an earthbound observer; it feels solid, stable, and stationary.
Ancient Greek, ancient Roman, and medieval philosophers usually combined the geocentric model with a spherical Earth, in contrast to the older flat-Earth model implied in some mythology. The ancient Jewish Babylonian uranography pictured a flat Earth with a dome-shaped, rigid canopy called the firmament placed over it (רקיע- rāqîa'). However, the Greek astronomer and mathematician Aristarchus of Samos
(c. 310 – c. 230 BC) developed a heliocentric model placing all of the
then-known planets in their correct order around the Sun. The ancient Greeks believed that the motions of the planets were circular, a view that was not challenged in Western culture until the 17th century, when Johannes Kepler postulated that orbits were heliocentric and elliptical (Kepler's first law of planetary motion). In 1687 Newton showed that elliptical orbits could be derived from his laws of gravitation.
The astronomical predictions of Ptolemy's geocentric model, developed in the 2nd century CE, served as the basis for preparing astrological and astronomical charts for over 1500 years. The geocentric model held sway into the early modern age, but from the late 16th century onward, it was gradually superseded by the heliocentric model of Copernicus (1473-1543), Galileo (1564-1642), and Kepler
(1571-1630). There was much resistance to the transition between these
two theories. Some felt that a new, unknown theory could not subvert an
accepted consensus for geocentrism.
Ancient Greece
Illustration of Anaximander's models of the universe. On the left, summer; on the right, winter.
The geocentric model entered Greek astronomy and philosophy at an early point; it can be found in pre-Socratic philosophy. In the 6th century BC, Anaximander
proposed a cosmology with Earth shaped like a section of a pillar (a
cylinder), held aloft at the center of everything. The Sun, Moon, and
planets were holes in invisible wheels surrounding Earth; through the
holes, humans could see concealed fire. About the same time, Pythagoras
thought that the Earth was a sphere (in accordance with observations of
eclipses), but not at the center; he believed that it was in motion
around an unseen fire. Later these views were combined, so most educated
Greeks from the 4th century BC on thought that the Earth was a sphere
at the center of the universe.
In the 4th century BC, two influential Greek philosophers, Plato and his student Aristotle,
wrote works based on the geocentric model. According to Plato, the
Earth was a sphere, stationary at the center of the universe. The stars
and planets were carried around the Earth on spheres or circles,
arranged in the order (outwards from the center): Moon, Sun, Venus,
Mercury, Mars, Jupiter, Saturn, fixed stars, with the fixed stars
located on the celestial sphere. In his "Myth of Er", a section of the Republic, Plato describes the cosmos as the Spindle of Necessity, attended by the Sirens and turned by the three Fates. Eudoxus of Cnidus, who worked with Plato, developed a less mythical, more mathematical explanation of the planets' motion based on Plato's dictum stating that all phenomena in the heavens can be explained with uniform circular motion. Aristotle elaborated on Eudoxus' system.
In the fully developed Aristotelian system, the spherical Earth
is at the center of the universe, and all other heavenly bodies are
attached to 47–55 transparent, rotating spheres surrounding the Earth,
all concentric with it. (The number is so high because several spheres
are needed for each planet.) These spheres, known as crystalline
spheres, all moved at different uniform speeds to create the revolution
of bodies around the Earth. They were composed of an incorruptible
substance called aether.
Aristotle believed that the Moon was in the innermost sphere and
therefore touches the realm of Earth, causing the dark spots (macula) and the ability to go through lunar phases.
He further described his system by explaining the natural tendencies
of the terrestrial elements: Earth, water, fire, air, as well as
celestial aether. His system held that Earth was the heaviest element,
with the strongest movement towards the center, thus water formed a
layer surrounding the sphere of Earth. The tendency of air and fire, on
the other hand, was to move upwards, away from the center, with fire
being lighter than air. Beyond the layer of fire, were the solid spheres
of aether in which the celestial bodies were embedded. They,
themselves, were also entirely composed of aether.
Adherence to the geocentric model stemmed largely from several
important observations. First of all, if the Earth did move, then one
ought to be able to observe the shifting of the fixed stars due to stellar parallax. In short, if the Earth was moving, the shapes of the constellations
should change considerably over the course of a year. If they did not
appear to move, the stars are either much farther away than the Sun and
the planets than previously conceived, making their motion undetectable,
or in reality they are not moving at all. Because the stars were
actually much further away than Greek astronomers postulated (making
movement extremely subtle), stellar parallax was not detected until the 19th century.
Therefore, the Greeks chose the simpler of the two explanations.
Another observation used in favor of the geocentric model at the time
was the apparent consistency of Venus' luminosity, which implies that it
is usually about the same distance from Earth, which in turn is more
consistent with geocentrism than heliocentrism. In reality, that is
because the loss of light caused by Venus' phases compensates for the
increase in apparent size caused by its varying distance from Earth.
Objectors to heliocentrism noted that terrestrial bodies naturally tend
to come to rest as near as possible to the center of the Earth. Further
barring the opportunity to fall closer the center, terrestrial bodies
tend not to move unless forced by an outside object, or transformed to a
different element by heat or moisture.
Atmospheric explanations for many phenomena were preferred
because the Eudoxan–Aristotelian model based on perfectly concentric
spheres was not intended to explain changes in the brightness of the
planets due to a change in distance.
Eventually, perfectly concentric spheres were abandoned as it was
impossible to develop a sufficiently accurate model under that ideal.
However, while providing for similar explanations, the later deferent and epicycle model was flexible enough to accommodate observations for many centuries.
Ptolemaic model
The basic elements of Ptolemaic astronomy, showing a planet on an epicycle with an eccentric deferent and an equant point. The Green shaded area is the celestial sphere which the planet occupies.
Although the basic tenets of Greek geocentrism were established by
the time of Aristotle, the details of his system did not become
standard. The Ptolemaic system, developed by the Hellenistic astronomer Claudius Ptolemaeus in the 2nd century AD finally standardised geocentrism. His main astronomical work, the Almagest, was the culmination of centuries of work by Hellenic, Hellenistic and Babylonian astronomers. For over a millennium European and Islamic astronomers
assumed it was the correct cosmological model. Because of its
influence, people sometimes wrongly think the Ptolemaic system is
identical with the geocentric model.
Ptolemy argued that the Earth was a sphere in the center of the
universe, from the simple observation that half the stars were above the
horizon and half were below the horizon at any time (stars on rotating
stellar sphere), and the assumption that the stars were all at some
modest distance from the center of the universe. If the Earth was
substantially displaced from the center, this division into visible and
invisible stars would not be equal.
Ptolemaic system
Pages from 1550 Annotazione on Sacrobosco's De sphaera mundi, showing the Ptolemaic system.
In the Ptolemaic system, each planet is moved by a system of two spheres: one called its deferent; the other, its epicycle.
The deferent is a circle whose center point, called the eccentric and
marked in the diagram with an X, is distant from the Earth. The original
purpose of the eccentric was to account for the difference in length of
the seasons (northern autumn was about five days shorter than spring
during this time period) by placing the Earth away from the center of
rotation of the rest of the universe. Another sphere, the epicycle, is
embedded inside the deferent sphere and is represented by the smaller
dotted line to the right. A given planet then moves around the epicycle
at the same time the epicycle moves along the path marked by the
deferent. These combined movements cause the given planet to move closer
to and further away from the Earth at different points in its orbit,
and explained the observation that planets slowed down, stopped, and
moved backward in retrograde motion, and then again reversed to resume normal, or prograde, motion.
The deferent-and-epicycle model had been used by Greek
astronomers for centuries along with the idea of the eccentric (a
deferent which center is slightly away from the Earth), which was even
older. In the illustration, the center of the deferent is not the Earth
but the spot marked X, making it eccentric (from the Greek ἐκ ec- meaning "from," and κέντρον kentron
meaning "center"), from which the spot takes its name. Unfortunately,
the system that was available in Ptolemy's time did not quite match observations,
even though it was improved over Hipparchus' system. Most noticeably
the size of a planet's retrograde loop (especially that of Mars) would
be smaller, and sometimes larger, than expected, resulting in positional
errors of as much as 30 degrees. To alleviate the problem, Ptolemy
developed the equant.
The equant was a point near the center of a planet's orbit which, if
you were to stand there and watch, the center of the planet's epicycle
would always appear to move at uniform speed; all other locations would
see non-uniform speed, like on the Earth. By using an equant, Ptolemy
claimed to keep motion which was uniform and circular, although it
departed from the Platonic ideal of uniform circular motion.
The resultant system, which eventually came to be widely accepted in
the west, seems unwieldy to modern astronomers; each planet required an
epicycle revolving on a deferent, offset by an equant which was
different for each planet. It predicted various celestial motions,
including the beginning and end of retrograde motion, to within a
maximum error of 10 degrees, considerably better than without the
equant.
The model with epicycles is in fact a very good model of an
elliptical orbit with low eccentricity. The well known ellipse shape
does not appear to a noticeable extent when the eccentricity is less
than 5%, but the offset distance of the "center" (in fact the focus
occupied by the sun) is very noticeable even with low eccentricities as
possessed by the planets.
To summarize, Ptolemy devised a system that was compatible with
Aristotelian philosophy and managed to track actual observations and
predict future movement mostly to within the limits of the next 1000
years of observations. The observed motions and his mechanisms for
explaining them include:
The Ptolemaic System
Object(s)
Observation
Modeling mechanism
Stars
Westward motion of entire sky in ~24 hrs ("first motion")
The geocentric model was eventually replaced by the heliocentric model. Copernican heliocentrism
could remove Ptolemy's epicycles because the retrograde motion could be
seen to be the result of the combination of Earth and planet movement
and speeds. Copernicus felt strongly that equants were a violation of
Aristotelian purity, and proved that replacement of the equant with a
pair of new epicycles was entirely equivalent. Astronomers often
continued using the equants instead of the epicycles because the former
was easier to calculate, and gave the same result.
It has been determined, in fact, that the Copernican, Ptolemaic and even the Tychonic
models provided identical results to identical inputs. They are
computationally equivalent. It wasn't until Kepler demonstrated a
physical observation that could show that the physical sun is directly
involved in determining an orbit that a new model was required.
The Ptolemaic order of spheres from Earth outward is:
Ptolemy did not invent or work out this order, which aligns with the ancient Seven Heavens religious cosmology
common to the major Eurasian religious traditions. It also follows the
decreasing orbital periods of the Moon, Sun, planets and stars.
Persian & Arab astronomy and geocentrism
Muslim astronomers generally accepted the Ptolemaic system and the geocentric model, but by the 10th century texts appeared regularly whose subject matter was doubts concerning Ptolemy (shukūk). Several Muslim scholars questioned the Earth's apparent immobility and centrality within the universe. Some Muslim astronomers believed that the Earth rotates around its axis, such as Abu Sa'id al-Sijzi (d. circa 1020). According to al-Biruni, Sijzi invented an astrolabe called al-zūraqī
based on a belief held by some of his contemporaries "that the motion
we see is due to the Earth's movement and not to that of the sky." The prevalence of this view is further confirmed by a reference from the 13th century which states:
According to the geometers [or engineers] (muhandisīn),
the Earth is in constant circular motion, and what appears to be the
motion of the heavens is actually due to the motion of the Earth and not
the stars.
Early in the 11th century Alhazen wrote a scathing critique of Ptolemy's model in his Doubts on Ptolemy (c. 1028), which some have interpreted to imply he was criticizing Ptolemy's geocentrism, but most agree that he was actually criticizing the details of Ptolemy's model rather than his geocentrism.
In the 12th century, Arzachel departed from the ancient Greek idea of uniform circular motions by hypothesizing that the planet Mercury moves in an elliptic orbit, while Alpetragius proposed a planetary model that abandoned the equant, epicycle and eccentric mechanisms, though this resulted in a system that was mathematically less accurate.
Alpetragius also declared the Ptolemaic system as an imaginary model
that was successful at predicting planetary positions but not real or
physical. His alternative system spread through most of Europe during
the 13th century.
Fakhr al-Din al-Razi (1149–1209), in dealing with his conception of physics and the physical world in his Matalib, rejects the Aristotelian and Avicennian notion of the Earth's centrality within the universe, but instead argues that there are "a thousand thousand worlds (alfa alfi 'awalim)
beyond this world such that each one of those worlds be bigger and more
massive than this world as well as having the like of what this world
has." To support his theological argument, he cites the Qur'anic verse, "All praise belongs to God, Lord of the Worlds," emphasizing the term "Worlds."
The "Maragha Revolution" refers to the Maragha school's
revolution against Ptolemaic astronomy. The "Maragha school" was an
astronomical tradition beginning in the Maragha observatory and continuing with astronomers from the Damascus mosque and Samarkand observatory. Like their Andalusian predecessors, the Maragha astronomers attempted to solve the equant problem (the circle around whose circumference a planet or the center of an epicycle
was conceived to move uniformly) and produce alternative configurations
to the Ptolemaic model without abandoning geocentrism. They were more
successful than their Andalusian predecessors in producing non-Ptolemaic
configurations which eliminated the equant and eccentrics, were more
accurate than the Ptolemaic model in numerically predicting planetary
positions, and were in better agreement with empirical observations. The most important of the Maragha astronomers included Mo'ayyeduddin Urdi (d. 1266), Nasīr al-Dīn al-Tūsī (1201–1274), Qutb al-Din al-Shirazi (1236–1311), Ibn al-Shatir (1304–1375), Ali Qushji (c. 1474), Al-Birjandi (d. 1525), and Shams al-Din al-Khafri (d. 1550). Ibn al-Shatir, the Damascene astronomer (1304–1375 AD) working at the Umayyad Mosque, wrote a major book entitled Kitab Nihayat al-Sul fi Tashih al-Usul (A Final Inquiry Concerning the Rectification of Planetary Theory) on a theory which departs largely from the Ptolemaic system known at that time. In his book, Ibn al-Shatir, an Arab astronomer of the fourteenth century,
E. S. Kennedy wrote "what is of most interest, however, is that Ibn
al-Shatir's lunar theory, except for trivial differences in parameters,
is identical with that of Copernicus
(1473–1543 AD)." The discovery that the models of Ibn al-Shatir are
mathematically identical to those of Copernicus suggests the possible
transmission of these models to Europe. At the Maragha and Samarkand observatories, the Earth's rotation was discussed by al-Tusi and Ali Qushji (b. 1403); the arguments and evidence they used resemble those used by Copernicus to support the Earth's motion.
However, the Maragha school never made the paradigm shift to heliocentrism. The influence of the Maragha school on Copernicus
remains speculative, since there is no documentary evidence to prove
it. The possibility that Copernicus independently developed the Tusi
couple remains open, since no researcher has yet demonstrated that he
knew about Tusi's work or that of the Maragha school.
Geocentrism and rival systems
This drawing from an Icelandic manuscript dated around 1750 illustrates the geocentric model.
Not all Greeks agreed with the geocentric model. The Pythagorean
system has already been mentioned; some Pythagoreans believed the Earth
to be one of several planets going around a central fire. Hicetas and Ecphantus, two Pythagoreans of the 5th century BC, and Heraclides Ponticus in the 4th century BC, believed that the Earth rotated on its axis but remained at the center of the universe. Such a system still qualifies as geocentric. It was revived in the Middle Ages by Jean Buridan.
Heraclides Ponticus was once thought to have proposed that both Venus
and Mercury went around the Sun rather than the Earth, but this is no
longer accepted. Martianus Capella definitely put Mercury and Venus in orbit around the Sun. Aristarchus of Samos was the most radical. He wrote a work, which has not survived, on heliocentrism, saying that the Sun was at the center of the universe, while the Earth and other planets revolved around it. His theory was not popular, and he had one named follower, Seleucus of Seleucia.
In 1543, the geocentric system met its first serious challenge with the publication of Copernicus' De revolutionibus orbium coelestium (On the Revolutions of the Heavenly Spheres),
which posited that the Earth and the other planets instead revolved
around the Sun. The geocentric system was still held for many years
afterwards, as at the time the Copernican system did not offer better
predictions than the geocentric system, and it posed problems for both natural philosophy
and scripture. The Copernican system was no more accurate than
Ptolemy's system, because it still used circular orbits. This was not
altered until Johannes Kepler postulated that they were elliptical (Kepler's first law of planetary motion).
With the invention of the telescope in 1609, observations made by Galileo Galilei (such as that Jupiter
has moons) called into question some of the tenets of geocentrism but
did not seriously threaten it. Because he observed dark "spots" on the
Moon, craters, he remarked that the moon was not a perfect celestial
body as had been previously conceived. This was the first time someone
could see imperfections on a celestial body that was supposed to be
composed of perfect aether.
As such, because the Moon's imperfections could now be related to
those seen on Earth, one could argue that neither was unique: rather,
they were both just celestial bodies made from Earth-like material.
Galileo could also see the moons of Jupiter, which he dedicated to Cosimo II de' Medici, and stated that they orbited around Jupiter, not Earth.
This was a significant claim as it would mean not only that not
everything revolved around Earth as stated in the Ptolemaic model, but
also showed a secondary celestial body could orbit a moving celestial
body, strengthening the heliocentric argument that a moving Earth could
retain the Moon.
Galileo's observations were verified by other astronomers of the time
period who quickly adopted use of the telescope, including Christoph Scheiner, Johannes Kepler, and Giovan Paulo Lembo.
Phases of Venus
In December 1610, Galileo Galilei used his telescope to observe that Venus showed all phases, just like the Moon.
He thought that while this observation was incompatible with the
Ptolemaic system, it was a natural consequence of the heliocentric
system.
However, Ptolemy placed Venus' deferent and epicycle
entirely inside the sphere of the Sun (between the Sun and Mercury),
but this was arbitrary; he could just as easily have swapped Venus and
Mercury and put them on the other side of the Sun, or made any other
arrangement of Venus and Mercury, as long as they were always near a
line running from the Earth through the Sun, such as placing the center
of the Venus epicycle near the Sun. In this case, if the Sun is the
source of all the light, under the Ptolemaic system:
If Venus is between Earth and the Sun, the phase of Venus must always be crescent or all dark.
If Venus is beyond the Sun, the phase of Venus must always be gibbous or full.
But Galileo saw Venus at first small and full, and later large and crescent.
In
this depiction of the Tychonic system, the objects on blue orbits (the
Moon and the Sun) revolve around the Earth. The objects on orange orbits
(Mercury, Venus, Mars, Jupiter, and Saturn) revolve around the Sun.
Around all is a sphere of stars, which rotates.
This showed that with a Ptolemaic cosmology, the Venus epicycle can
be neither completely inside nor completely outside of the orbit of the
Sun. As a result, Ptolemaics abandoned the idea that the epicycle of
Venus was completely inside the Sun, and later 17th-century competition
between astronomical cosmologies focused on variations of Tycho Brahe's Tychonic system
(in which the Earth was still at the center of the universe, and around
it revolved the Sun, but all other planets revolved around the Sun in
one massive set of epicycles), or variations on the Copernican system.
Gravitation
Johannes Kepler analysed Tycho Brahe's famously accurate observations and afterwards constructed his three laws
in 1609 and 1619, based on a heliocentric view where the planets move
in elliptical paths. Using these laws, he was the first astronomer to
successfully predict a transit of Venus
for the year 1631. The change from circular orbits to elliptical
planetary paths dramatically improved the accuracy of celestial
observations and predictions. Because the heliocentric model devised by
Copernicus was no more accurate than Ptolemy's system, new observations
were needed to persuade those who still adhered to the geocentric model.
However, Kepler's laws based on Brahe's data became a problem which
geocentrists could not easily overcome.
In 1687, Isaac Newton stated the law of universal gravitation, described earlier as a hypothesis by Robert Hooke and others. His main achievement was to mathematically derive Kepler's laws of planetary motion from the law of gravitation, thus helping to prove the latter. This introduced gravitation
as the force which both kept the Earth and planets moving through the
universe and also kept the atmosphere from flying away. The theory of
gravity allowed scientists to rapidly construct a plausible heliocentric
model for the Solar System. In his Principia,
Newton explained his theory of how gravity, previously thought to be a
mysterious, unexplained occult force, directed the movements of
celestial bodies, and kept our Solar System in working order. His
descriptions of centripetal force were a breakthrough in scientific thought, using the newly developed mathematical discipline of differential calculus,
finally replacing the previous schools of scientific thought, which had
been dominated by Aristotle and Ptolemy. However, the process was
gradual.
Several empirical tests
of Newton's theory, explaining the longer period of oscillation of a
pendulum at the equator and the differing size of a degree of latitude,
would gradually become available between 1673 and 1738. In addition, stellar aberration was observed by Robert Hooke in 1674, and tested in a series of observations by Jean Picard over a period of ten years, finishing in 1680. However, it was not explained until 1729, when James Bradley provided an approximate explanation in terms of the Earth's revolution about the Sun.
In 1838, astronomer Friedrich Wilhelm Bessel measured the parallax of the star 61 Cygni
successfully, and disproved Ptolemy's claim that parallax motion did
not exist. This finally confirmed the assumptions made by Copernicus,
providing accurate, dependable scientific observations, and conclusively
displaying how distant stars are from Earth.
A geocentric frame is useful for many everyday activities and
most laboratory experiments, but is a less appropriate choice for Solar
System mechanics and space travel. While a heliocentric frame
is most useful in those cases, galactic and extragalactic astronomy is
easier if the Sun is treated as neither stationary nor the center of the
universe, but rather rotating around the center of our galaxy, while in
turn our galaxy is also not at rest in the cosmic background.
Relativity
Albert Einstein and Leopold Infeld wrote in The Evolution of Physics (1938): "Can we formulate physical laws so that they are valid for all CS (=coordinate systems),
not only those moving uniformly, but also those moving quite
arbitrarily, relative to each other? If this can be done, our
difficulties will be over. We shall then be able to apply the laws of
nature to any CS. The struggle, so violent in the early days of science,
between the views of Ptolemy and Copernicus would then be quite
meaningless. Either CS could be used with equal justification. The two
sentences, 'the sun is at rest and the Earth moves', or 'the sun moves
and the Earth is at rest', would simply mean two different conventions
concerning two different CS.
Could we build a real relativistic physics valid in all CS; a physics in
which there would be no place for absolute, but only for relative,
motion? This is indeed possible!"
Despite giving more respectability to the geocentric view than Newtonian physics does,
relativity is not geocentric. Rather, relativity states that the Sun,
the Earth, the Moon, Jupiter, or any other point for that matter could
be chosen as a center of the Solar System with equal validity.
Relativity agrees with Newtonian predictions that regardless of
whether the Sun or the Earth are chosen arbitrarily as the center of the
coordinate system describing the Solar System, the paths of the planets
form (roughly) ellipses with respect to the Sun, not the Earth. With
respect to the average reference frame of the fixed stars,
the planets do indeed move around the Sun, which due to its much larger
mass, moves far less than its own diameter and the gravity of which is
dominant in determining the orbits of the planets (in other words, the
center of mass of the Solar System is near the center of the Sun). The
Earth and Moon are much closer to being a binary planet;
the center of mass around which they both rotate is still inside the
Earth, but is about 4,624 km (2,873 mi) or 72.6% of the Earth's radius
away from the centre of the Earth (thus closer to the surface than the
center).
What the principle of relativity points out is that correct
mathematical calculations can be made regardless of the reference frame
chosen, and these will all agree with each other as to the predictions
of actual motions of bodies with respect to each other. It is not
necessary to choose the object in the Solar System with the largest
gravitational field as the center of the coordinate system in order to
predict the motions of planetary bodies, though doing so may make
calculations easier to perform or interpret. A geocentric coordinate system can be more convenient when dealing only with bodies mostly influenced by the gravity of the Earth (such as artificial satellites and the Moon),
or when calculating what the sky will look like when viewed from Earth
(as opposed to an imaginary observer looking down on the entire Solar
System, where a different coordinate system might be more convenient).
Religious and contemporary adherence to geocentrism
The Ptolemaic model of the solar system held sway into the early modern age; from the late 16th century onward it was gradually replaced as the consensus description by the heliocentric model. Geocentrism as a separate religious belief, however, never completely died out. In the United States between 1870 and 1920, for example, various members of the Lutheran Church–Missouri Synod published articles disparaging Copernican astronomy and promoting geocentrism. However, in the 1902 Theological Quarterly,
A. L. Graebner observed that the synod had no doctrinal position on
geocentrism, heliocentrism, or any scientific model, unless it were to
contradict Scripture. He stated that any possible declarations of
geocentrists within the synod did not set the position of the church
body as a whole.
Articles arguing that geocentrism was the biblical perspective appeared in some early creation science newsletters pointing to some passages in the Bible,
which, when taken literally, indicate that the daily apparent motions
of the Sun and the Moon are due to their actual motions around the Earth
rather than due to the rotation of the Earth about its axis. For
example, in Joshua 10:12, the Sun and Moon are said to stop in the sky, and in Psalms the world is described as immobile. Psalms 93:1 says in part, "the world is established, firm and secure". Contemporary advocates for such religious beliefs include Robert Sungenis (author of the 2006 book Galileo Was Wrong).
These people subscribe to the view that a plain reading of the Bible
contains an accurate account of the manner in which the universe was
created and requires a geocentric worldview. Most contemporary creationist organizations reject such perspectives.
Polls
According to a report released in 2014 by the National Science Foundation, 26% of Americans surveyed believe that the sun revolves around the Earth.
Morris Berman
quotes a 2006 survey that show currently some 20% of the U.S.
population believe that the Sun goes around the Earth (geocentricism)
rather than the Earth goes around the Sun (heliocentricism), while a
further 9% claimed not to know. Polls conducted by Gallup in the 1990s found that 16% of Germans, 18% of Americans and 19% of Britons hold that the Sun revolves around the Earth. A study conducted in 2005 by Jon D. Miller of Northwestern University, an expert in the public understanding of science and technology, found that about 20%, or one in five, of American adults believe that the Sun orbits the Earth. According to 2011 VTSIOM poll, 32% of Russians believe that the Sun orbits the Earth.
Historical positions of the Roman Catholic hierarchy
The famous Galileo affair pitted the geocentric model against the claims of Galileo.
In regards to the theological basis for such an argument, two Popes
addressed the question of whether the use of phenomenological language
would compel one to admit an error in Scripture. Both taught that it
would not. Pope Leo XIII (1878–1903) wrote:
we have to contend against those
who, making an evil use of physical science, minutely scrutinize the
Sacred Book in order to detect the writers in a mistake, and to take
occasion to vilify its contents. ... There can never, indeed, be any
real discrepancy between the theologian and the physicist, as long as
each confines himself within his own lines, and both are careful, as St.
Augustine warns us, "not to make rash assertions, or to assert what is
not known as known". If dissension should arise between them, here is
the rule also laid down by St. Augustine, for the theologian: "Whatever
they can really demonstrate to be true of physical nature, we must show
to be capable of reconciliation with our Scriptures; and whatever they
assert in their treatises which is contrary to these Scriptures of ours,
that is to Catholic faith, we must either prove it as well as we can to
be entirely false, or at all events we must, without the smallest
hesitation, believe it to be so." To understand how just is the rule
here formulated we must remember, first, that the sacred writers, or to
speak more accurately, the Holy Ghost "Who spoke by them, did not intend
to teach men these things (that is to say, the essential nature of the
things of the visible universe), things in no way profitable unto
salvation." Hence they did not seek to penetrate the secrets of nature,
but rather described and dealt with things in more or less figurative
language, or in terms which were commonly used at the time, and which in
many instances are in daily use at this day, even by the most eminent
men of science. Ordinary speech primarily and properly describes what
comes under the senses; and somewhat in the same way the sacred
writers-as the Angelic Doctor also reminds us – "went by what sensibly
appeared", or put down what God, speaking to men, signified, in the way
men could understand and were accustomed to.
Maurice Finocchiaro, author of a book on the Galileo affair, notes
that this is "a view of the relationship between biblical interpretation
and scientific investigation that corresponds to the one advanced by
Galileo in the "Letter to the Grand Duchess Christina". Pope Pius XII (1939–1958) repeated his predecessor's teaching:
The first and greatest care of Leo
XIII was to set forth the teaching on the truth of the Sacred Books and
to defend it from attack. Hence with grave words did he proclaim that
there is no error whatsoever if the sacred writer, speaking of things of
the physical order "went by what sensibly appeared" as the Angelic
Doctor says, speaking either "in figurative language, or in terms which
were commonly used at the time, and which in many instances are in daily
use at this day, even among the most eminent men of science". For "the
sacred writers, or to speak more accurately – the words are St.
Augustine's – the Holy Spirit, Who spoke by them, did not intend to
teach men these things – that is the essential nature of the things of
the universe – things in no way profitable to salvation"; which
principle "will apply to cognate sciences, and especially to history",
that is, by refuting, "in a somewhat similar way the fallacies of the
adversaries and defending the historical truth of Sacred Scripture from
their attacks".
In 1664, Pope Alexander VII republished the Index Librorum Prohibitorum (List of Prohibited Books) and attached the various decrees connected with those books, including those concerned with heliocentrism. He stated in a Papal Bull that his purpose in doing so was that "the succession of things done from the beginning might be made known [quo rei ab initio gestae series innotescat]".
The position of the curia evolved slowly over the centuries
towards permitting the heliocentric view. In 1757, during the papacy of
Benedict XIV, the Congregation of the Index withdrew the decree which
prohibited all books teaching the Earth's motion, although the Dialogue
and a few other books continued to be explicitly included. In 1820, the
Congregation of the Holy Office, with the pope's approval, decreed that
Catholic astronomer Giuseppe Settele
was allowed to treat the Earth's motion as an established fact and
removed any obstacle for Catholics to hold to the motion of the Earth:
The Assessor of the Holy Office has
referred the request of Giuseppe Settele, Professor of Optics and
Astronomy at La Sapienza University, regarding permission to publish his
work Elements of Astronomy in which he espouses the common opinion of
the astronomers of our time regarding the Earth’s daily and yearly
motions, to His Holiness through Divine Providence, Pope Pius VII.
Previously, His Holiness had referred this request to the Supreme Sacred
Congregation and concurrently to the consideration of the Most Eminent
and Most Reverend General Cardinal Inquisitor. His Holiness has decreed
that no obstacles exist for those who sustain Copernicus' affirmation
regarding the Earth's movement in the manner in which it is affirmed
today, even by Catholic authors. He has, moreover, suggested the
insertion of several notations into this work, aimed at demonstrating
that the above mentioned affirmation [of Copernicus], as it has come to
be understood, does not present any difficulties; difficulties that
existed in times past, prior to the subsequent astronomical observations
that have now occurred. [Pope Pius VII] has also recommended that the
implementation [of these decisions] be given to the Cardinal Secretary
of the Supreme Sacred Congregation and Master of the Sacred Apostolic
Palace. He is now appointed the task of bringing to an end any concerns
and criticisms regarding the printing of this book, and, at the same
time, ensuring that in the future, regarding the publication of such
works, permission is sought from the Cardinal Vicar whose signature will
not be given without the authorization of the Superior of his Order.
In 1822, the Congregation of the Holy Office removed the prohibition
on the publication of books treating of the Earth's motion in accordance
with modern astronomy and Pope Pius VII ratified the decision:
The most excellent [cardinals] have
decreed that there must be no denial, by the present or by future
Masters of the Sacred Apostolic Palace, of permission to print and to
publish works which treat of the mobility of the Earth and of the
immobility of the sun, according to the common opinion of modern
astronomers, as long as there are no other contrary indications, on the
basis of the decrees of the Sacred Congregation of the Index of 1757 and
of this Supreme [Holy Office] of 1820; and that those who would show
themselves to be reluctant or would disobey, should be forced under
punishments at the choice of [this] Sacred Congregation, with derogation
of [their] claimed privileges, where necessary.
The 1835 edition of the Catholic List of Prohibited Books for the first time omits the Dialogue from the list. In his 1921 papal encyclical, In praeclara summorum, Pope Benedict XV
stated that, "though this Earth on which we live may not be the center
of the universe as at one time was thought, it was the scene of the
original happiness of our first ancestors, witness of their unhappy
fall, as too of the Redemption of mankind through the Passion and Death
of Jesus Christ". In 1965 the Second Vatican Council
stated that, "Consequently, we cannot but deplore certain habits of
mind, which are sometimes found too among Christians, which do not
sufficiently attend to the rightful independence of science and which,
from the arguments and controversies they spark, lead many minds to
conclude that faith and science are mutually opposed." The footnote on this statement is to Msgr. Pio Paschini's, Vita e opere di Galileo Galilei, 2 volumes, Vatican Press (1964). Pope John Paul II regretted the treatment which Galileo received, in a speech to the Pontifical Academy of Sciences in 1992. The Pope declared the incident to be based on a "tragic mutual miscomprehension". He further stated:
Cardinal Poupard has also reminded
us that the sentence of 1633 was not irreformable, and that the debate
which had not ceased to evolve thereafter, was closed in 1820 with the
imprimatur given to the work of Canon Settele. ... The error of the
theologians of the time, when they maintained the centrality of the
Earth, was to think that our understanding of the physical world's
structure was, in some way, imposed by the literal sense of Sacred
Scripture. Let us recall the celebrated saying attributed to Baronius
"Spiritui Sancto mentem fuisse nos docere quomodo ad coelum eatur, non
quomodo coelum gradiatur". In fact, the Bible does not concern itself
with the details of the physical world, the understanding of which is
the competence of human experience and reasoning. There exist two realms
of knowledge, one which has its source in Revelation and one which
reason can discover by its own power. To the latter belong especially
the experimental sciences and philosophy. The distinction between the
two realms of knowledge ought not to be understood as opposition.
Orthodox Judaism
A few Orthodox Jewish leaders maintain a geocentric model of the universe based on the aforementioned Biblical verses and an interpretation of Maimonides to the effect that he ruled that the Earth is orbited by the Sun. The Lubavitcher Rebbe also explained that geocentrism is defensible based on the theory of relativity,
which establishes that "when two bodies in space are in motion relative
to one another, ... science declares with absolute certainty that from
the scientific point of view both possibilities are equally valid,
namely that the Earth revolves around the sun, or the sun revolves
around the Earth", although he also went on to refer to people who
believed in geocentrism as "remaining in the world of Copernicus".
The Zohar states: "The entire world and those upon it, spin round
in a circle like a ball, both those at the bottom of the ball and those
at the top. All God's creatures, wherever they live on the different
parts of the ball, look different (in color, in their features) because
the air is different in each place, but they stand erect as all other
human beings, therefore, there are places in the world where, when some
have light, others have darkness; when some have day, others have
night."
While geocentrism is important in Maimonides' calendar calculations,
the great majority of Jewish religious scholars, who accept the
divinity of the Bible and accept many of his rulings as legally binding,
do not believe that the Bible or Maimonides command a belief in
geocentrism.
Islam
After the translation movement led by the Mu'tazila, which included the translation of Almagest from Latin to Arabic, Muslims adopted and refined the geocentric model of Ptolemy, which they believed correlated with the teachings of Islam.
Prominent cases of modern geocentrism are very isolated. Very few
individuals promoted a geocentric view of the universe. One of them was
Ahmed Raza Khan Barelvi, a Sunni scholar of Indian subcontinent. He rejected the heliocentric model and wrote a book that explains the movement of the sun, moon and other planets around the Earth.
Planetariums
The geocentric (Ptolemaic) model of the solar system is still of interest to planetarium
makers, as, for technical reasons, a Ptolemaic-type motion for the
planet light apparatus has some advantages over a Copernican-type
motion. The celestial sphere, still used for teaching purposes and sometimes for navigation, is also based on a geocentric system which in effect ignores parallax. However this effect is negligible at the scale of accuracy that applies to a planetarium.
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