T cell

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/T_cell 

T lymphocyte cell
Scanning electron micrograph of a human T cell
Scanning electron micrograph of a red blood cell (left), a platelet (center), and a T lymphocyte (right); colorized
Details
System	Immune system
Identifiers
Latin	lymphocytus T
MeSH	D013601
TH	H2.00.04.1.02007
FMA	62870

A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.

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.

Conventional adaptive T cells

Helper CD4+ T cells

Main article: T helper cell

T helper cells (T_H 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 peptide antigens 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.

CD4+ Helper T cell subsets

Cell type	Cytokines Produced	Key Transcription Factor	Role in immune defense	Related diseases
Th1	IFNγ	Tbet	Produce an inflammatory response, key for defense against intracellular bacteria, viruses and cancer.	MS, Type 1 diabetes
Th2	IL-4	GATA-3	Aid the differentiation and antibody production by B cells	Asthma and other allergic diseases
Th17	IL-17	RORγt	Defense against gut pathogens and at mucosal barriers	MS, Rheumatoid Arthritis, Psoriasis
Th9	IL-9	IRF4, PU.1	Defense against helminths (parasitic worms)	Multiple Sclerosis
Tfh	IL-21, IL-4	Bcl-6	Help B cells produce antibodies	Asthma and other allergic diseases

Cytotoxic CD8+ T cells

Main article: Cytotoxic T cell

 

Superresolution image of a group of cytotoxic T cells surrounding a cancer cell

Cytotoxic T cells (T_C 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.

Memory T cells

Main article: Memory T cell

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 (T_CM 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 (T_EM cells and T_EMRA 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. T_EMRA 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 (T_RM) occupy tissues (skin, lung, etc.) without recirculating. One cell surface marker that has been associated with T_RM 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 CD4+ T cells

Main article: Regulatory T cell

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⁺ T_reg cells have been described — FOXP3⁺ T_reg cells and FOXP3⁻ T_reg 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 factor FOXP3 which can be used to identify the cells. Mutations of the FOXP3 gene can prevent regulatory T cell development, causing the fatal autoimmune disease IPEX.

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 cell

Main article: Natural killer T cell

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 cells

Main article: Mucosal associated invariant T cell

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

Main article: Gamma delta T cell

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.

Activation

See also: T-cell receptor § Signaling pathway

 

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.

In spring 2014, the T-Cell Activation in Space (TCAS) experiment was launched to the International Space Station on the SpaceX CRS-3 mission to study how "deficiencies in the human immune system are affected by a microgravity environment".

T cell activation is modulated by reactive oxygen species.

Antigen discrimination

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.

Clinical significance

Deficiency

Main article: T cell deficiency

Causes of T cell deficiency include lymphocytopenia of T cells and/or defects on function of individual T cells. Complete insufficiency of T cell function can result from hereditary conditions such as severe combined immunodeficiency (SCID), Omenn syndrome, and cartilage–hair hypoplasia. Causes of partial insufficiencies of T cell function include acquired immune deficiency syndrome (AIDS), and hereditary conditions such as DiGeorge syndrome (DGS), chromosomal breakage syndromes (CBSs), and B cell and T cell combined disorders such as ataxia-telangiectasia (AT) and Wiskott–Aldrich syndrome (WAS).

The main pathogens of concern in T cell deficiencies are intracellular pathogens, including Herpes simplex virus, Mycobacterium and Listeria. Also, fungal infections are also more common and severe in T cell deficiencies.

Cancer

Further information: T-cell lymphoma

Cancer of T cells is termed T-cell lymphoma, and accounts for perhaps one in ten cases of non-Hodgkin lymphoma. The main forms of T cell lymphoma are:

• Extranodal T cell lymphoma
• Cutaneous T cell lymphomas: Sézary syndrome and Mycosis fungoides
• Anaplastic large cell lymphoma
• Angioimmunoblastic T cell lymphoma

Exhaustion

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

See also: Immunosenescence

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.

Geocentric model

From Wikipedia, the free encyclopedia

https://en.wikipedia.org/wiki/Geocentric_model 

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")	Stars: Daily westward motion of sphere of stars, carrying all other spheres with it; normally ignored; other spheres have additional motions
Sun	Eastward motion yearly along ecliptic	Eastward motion of Sun's sphere in one year
Sun	Non-uniform rate along ecliptic (uneven seasons)	Eccentric orbit (Sun's deferent center off Earth)
Moon	Monthly eastward motion compared to stars	Monthly eastward motion of Moon's sphere
The 5 planets	General eastward motion through zodiac	Eastward motion of deferents; period set by observation of planet going around the ecliptic
Planets	Retrograde motion	Motion of epicycle in same direction as deferent. Period of epicycle is time between retrograde motions (synodic period).
Planets	Variations in speed through the zodiac	Eccentric per planet
Planets	Variations in retrograde timing	Equants per planet (Copernicus used a pair of epicycles instead)
Planets	Size of deferents, epicycles	Only ratio between radius of deferent and associated epicycle determined; absolute distances not determined in theory
Interior planets	Average greatest elongations of 23° (Mercury) and 46° (Venus)	Size of epicycles set by these angles, proportional to distances
Interior planets	Limited to movement near the Sun	Center their deferent centers along the Sun–Earth line
Exterior planets	Retrograde only at opposition, when brightest	Radii of epicycles aligned to the Sun–Earth line

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:

1. Moon
2. Mercury
3. Venus
4. Sun
5. Mars
6. Jupiter
7. Saturn
8. Fixed Stars
9. Primum Mobile ("First Moved")

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.

Copernican system

Main article: Copernican heliocentrism

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.

— Providentissimus Deus 18

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".

— Divino afflante Spiritu, 3

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.