T cells (thymus cells) and B cells (bone marrow- or bursa-derived cells) are the major cellular components of the adaptive immune response. T cells are involved in cell-mediated immunity, whereas B cells are primarily responsible for humoral immunity (relating to antibodies). The function of T cells and B cells is to recognize specific "non-self" antigens, during a process known as antigen presentation. Once they have identified an invader, the cells generate specific responses that are tailored maximally to eliminate specific pathogens or pathogen-infected cells. B cells respond to pathogens by producing large quantities of antibodies which then neutralize foreign objects like bacteria and viruses. In response to pathogens some T cells, called T helper cells, produce cytokines that direct the immune response, while other T cells, called cytotoxic T cells, produce toxic granules that contain powerful enzymes
which induce the death of pathogen-infected cells. Following
activation, B cells and T cells leave a lasting legacy of the antigens
they have encountered, in the form of memory cells. Throughout
the lifetime of an animal, these memory cells will "remember" each
specific pathogen encountered, and are able to mount a strong and rapid
response if the same pathogen is detected again; this is known as
acquired immunity.
NK cells are a part of the innate immune system and play a major role in defending the host from tumors and virally infected cells. NK cells modulate the functions of other cells, including macrophages and T cells,
and distinguish infected cells and tumors from normal and uninfected
cells by recognizing changes of a surface molecule called MHC (major histocompatibility complex) class I. NK cells are activated in response to a family of cytokines called interferons. Activated NK cells release cytotoxic (cell-killing) granules which then destroy the altered cells.
They are named "natural killer cells" because they do not require prior
activation in order to kill cells which are missing MHC class I.
Dual expresser lymphocyte - X cell
The X lymphocyte is a reported cell type expressing both a B-cell receptor and T-cell receptor and is hypothesized to be implicated in type 1 diabetes. Its existence as a cell type has been challenged by two studies.
However, the authors of original article pointed to the fact that the
two studies have detected X cells by imaging microscopy and FACS as
described. Additional studies are obviously required to determine the nature and properties of X cells (also called dual expressers).
Mammalian stem cellsdifferentiate into several kinds of blood cell within the bone marrow. This process is called haematopoiesis.
All lymphocytes originate, during this process, from a common lymphoid
progenitor before differentiating into their distinct lymphocyte types.
The differentiation of lymphocytes follows various pathways in a
hierarchical fashion as well as in a more plastic fashion. The formation
of lymphocytes is known as lymphopoiesis. 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, (B for bursa) and not from bone marrow as commonly believed. T cells migrate to and mature in a distinct organ, called the thymus. Following maturation, the lymphocytes enter the circulation and peripheral lymphoid organs (e.g. the spleen and lymph nodes) where they survey for invading pathogens and/or tumor cells.
The lymphocytes involved in adaptive immunity (i.e. B and T cells) differentiate further after exposure to an antigen;
they form effector and memory lymphocytes. Effector lymphocytes
function to eliminate the antigen, either by releasing antibodies (in
the case of B cells), cytotoxic granules (cytotoxic T cells) or by signaling to other cells of the immune system (helper T cells). Memory T cells
remain in the peripheral tissues and circulation for an extended time
ready to respond to the same antigen upon future exposure; they live
weeks to several years, which is very long compared to other leukocytes.
It is impossible to distinguish between T cells and B cells in a peripheral blood smear. Normally, flow cytometry
testing is used for specific lymphocyte population counts. This can be
used to determine the percentage of lymphocytes that contain a
particular combination of specific cell surface proteins, such as immunoglobulins or cluster of differentiation (CD) markers or that produce particular proteins (for example, cytokines
using intracellular cytokine staining (ICCS)). In order to study the
function of a lymphocyte by virtue of the proteins it generates, other
scientific techniques like the ELISPOT or secretion assay techniques can be used.
Several lymphocytes seen collected around a tuberculous granuloma
A lymphocyte count is usually part of a peripheral complete blood cell count and is expressed as the percentage of lymphocytes to the total number of white blood cells counted.
A general increase in the number of lymphocytes is known as lymphocytosis, whereas a decrease is known as lymphocytopenia.
High
An increase in lymphocyte concentration is usually a sign of a viral infection (in some rare case, leukemias are found through an abnormally raised lymphocyte count in an otherwise normal person). A high lymphocyte count with a low neutrophil count might be caused by lymphoma. Pertussis toxin (PTx) of Bordetella pertussis,
formerly known as lymphocytosis-promoting factor, causes a decrease in
the entry of lymphocytes into lymph nodes, which can lead to a condition
known as lymphocytosis, with a complete lymphocyte count of over 4000
per μl
in adults or over 8000 per μl in children. This is unique in that many
bacterial infections illustrate neutrophil-predominance instead.
One basis for low T cell lymphocytes occurs when the human immunodeficiency virus (HIV) infects and destroys T cells (specifically, the CD4+ subgroup of T lymphocytes, which become helper T cells). Without the key defense that these T cells provide, the body becomes susceptible to opportunistic infections
that otherwise would not affect healthy people. The extent of HIV
progression is typically determined by measuring the percentage of CD4+ T cells in the patient's blood – HIV ultimately progresses to acquired immune deficiency syndrome (AIDS). The effects of other viruses or lymphocyte disorders can also often be estimated by counting the numbers of lymphocytes present in the blood.
In some cancers, such as melanoma and colorectal cancer, lymphocytes can migrate into and attack the tumor. This can sometimes lead to regression of the primary tumor.
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. 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.
In immunology, an antigen (Ag) is a molecule or molecular structure that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response. The term antigen originally referred to a substance that is an antibody generator. Antigens can be proteins, peptides (amino acid chains), polysaccharides (chains of monosaccharides/simple sugars), lipids, nucleic acids, or other biomolecules.
Antigens are recognized by antigen receptors, including
antibodies and T-cell receptors. Diverse antigen receptors are made by
cells of the immune system so that each cell has a specificity for a
single antigen. Upon exposure to an antigen, only the lymphocytes that
recognize that antigen are activated and expanded, a process known as clonal selection. In most cases, an antibody can only react to and bind one specific antigen; in some instances, however, antibodies may cross-react and bind more than one antigen.
The antigen may originate from within the body ("self-protein") or from the external environment ("non-self"). The immune system identifies and attacks "non-self" external antigens and usually does not react to self-protein due to negative selection of T cells in the thymus and B cells in the bone marrow.
Vaccines
are examples of antigens in an immunogenic form, which are
intentionally administered to a recipient to induce the memory function
of the adaptive immune system towards antigens of the pathogen invading that recipient. The vaccine for seasonal influenza is a common example.
Etymology
Paul Ehrlich coined the term antibody (in German Antikörper) in his side-chain theory at the end of the 19th century. In 1899, Ladislas Deutsch (László Detre)
(1874–1939) named the hypothetical substances halfway between bacterial
constituents and antibodies "substances immunogènes ou antigènes"
(antigenic or immunogenic substances). He originally believed those
substances to be precursors of antibodies, just as zymogen
is a precursor of an enzyme. But, by 1903, he understood that an
antigen induces the production of immune bodies (antibodies) and wrote
that the word antigen is a contraction of antisomatogen (Immunkörperbildner). The Oxford English Dictionary indicates that the logical construction should be "anti(body)-gen".
Terminology
Epitope – the distinct surface features of an antigen, its antigenic determinant. Antigenic
molecules, normally "large" biological polymers, usually present
surface features that can act as points of interaction for specific
antibodies. Any such feature constitutes an epitope. Most antigens have
the potential to be bound by multiple antibodies, each of which is
specific to one of the antigen's epitopes. Using the "lock and key"
metaphor, the antigen can be seen as a string of keys (epitopes) each of
which matches a different lock (antibody). Different antibody idiotypes, each have distinctly formed complementarity-determining regions.
Allergen – A substance capable of causing an allergic reaction .The (detrimental) reaction may result after exposure via ingestion, inhalation, injection, or contact with skin.
Superantigen – A class of antigens that cause non-specific activation of T-cells, resulting in polyclonal T-cell activation and massive cytokine release.
Tolerogen – A substance that invokes a specific immune non-responsiveness due to its molecular form. If its molecular form is changed, a tolerogen can become an immunogen.
Immunoglobulin-binding protein – Proteins such as protein A, protein G, and protein L
that are capable of binding to antibodies at positions outside of the
antigen-binding site. While antigens are the "target" of antibodies,
immunoglobulin-binding proteins "attack" antibodies.
T-dependent antigen – Antigens that require the assistance of T cells to induce the formation of specific antibodies.
T-independent antigen – Antigens that stimulate B cells directly.
Immunodominant antigens – Antigens that dominate (over all others from a pathogen)
in their ability to produce an immune response. T cell responses
typically are directed against a relatively few immunodominant epitopes,
although in some cases (e.g., infection with the malaria pathogen Plasmodium spp.) it is dispersed over a relatively large number of parasite antigens.
Antigen-presenting cells present antigens in the form of peptides on histocompatibility molecules.
The T cells selectively recognize the antigens; depending on the
antigen and the type of the histocompatibility molecule, different types
of T cells will be activated. For T-cell receptor (TCR) recognition,
the peptide must be processed into small fragments inside the cell and
presented by a major histocompatibility complex (MHC). The antigen cannot elicit the immune response without the help of an immunologic adjuvant. Similarly, the adjuvant component of vaccines plays an essential role in the activation of the innate immune system.
An immunogen is an antigen substance (or adduct) that is able to trigger a humoral (innate) or cell-mediated immune response.
It first initiates an innate immune response, which then causes the
activation of the adaptive immune response. An antigen binds the highly
variable immunoreceptor products (B-cell receptor or T-cell receptor)
once these have been generated. Immunogens are those antigens, termed immunogenic, capable of inducing an immune response.
At the molecular level, an antigen can be characterized by its ability to bind to an antibody's paratopes. Different antibodies have the potential to discriminate among specific epitopes present on the antigen surface. A hapten is a small molecule that can only induce an immune response when attached to a larger carrier molecule, such as a protein. Antigens can be proteins, polysaccharides, lipids, nucleic acids or other biomolecules. This includes parts (coats, capsules, cell walls, flagella, fimbriae, and toxins) of bacteria, viruses, and other microorganisms.
Non-microbial non-self antigens can include pollen, egg white, and
proteins from transplanted tissues and organs or on the surface of
transfused blood cells.
Sources
Antigens can be classified according to their source.
Exogenous antigens
Exogenous antigens are antigens that have entered the body from the outside, for example, by inhalation, ingestion or injection. The immune system's response to exogenous antigens is often subclinical. By endocytosis or phagocytosis, exogenous antigens are taken into the antigen-presenting cells (APCs) and processed into fragments. APCs then present the fragments to T helper cells (CD4+) by the use of class II histocompatibility
molecules on their surface. Some T cells are specific for the
peptide:MHC complex. They become activated and start to secrete
cytokines, substances that activate cytotoxic T lymphocytes (CTL), antibody-secreting B cells, macrophages and other particles.
Some antigens start out as exogenous and later become endogenous
(for example, intracellular viruses). Intracellular antigens can be
returned to circulation upon the destruction of the infected cell.
Endogenous antigens
Endogenous antigens are generated within normal cells as a result of normal cell metabolism, or because of viral or intracellular bacterial infection. The fragments are then presented on the cell surface in the complex with MHC class I molecules. If activated cytotoxic CD8+ T cells recognize them, the T cells secrete various toxins that cause the lysis or apoptosis of the infected cell. In order to keep the cytotoxic cells from killing cells just for presenting self-proteins, the cytotoxic cells (self-reactive T cells) are deleted as a result of tolerance (negative selection). Endogenous antigens include xenogenic (heterologous), autologous and idiotypic or allogenic (homologous) antigens. Sometimes antigens are part of the host itself in an autoimmune disease.
Autoantigens
An autoantigen is usually a self-protein or protein complex (and sometimes DNA or RNA) that is recognized by the immune system of patients suffering from a specific autoimmune disease. Under normal conditions, these self-proteins
should not be the target of the immune system, but in autoimmune
diseases, their associated T cells are not deleted and instead attack.
Neoantigens
Neoantigens are those that are entirely absent from the normal human genome. As compared with nonmutated self-proteins,
neoantigens are of relevance to tumor control, as the quality of the T
cell pool that is available for these antigens is not affected by
central T cell tolerance. Technology to systematically analyze T cell
reactivity against neoantigens became available only recently.
Neoantigens can be directly detected and quantified through a method
called MANA-SRM developed by a molecular diagnostics company, Complete
Omics Inc., through collaborating with a team in Johns Hopkins
University School of Medicine.
Viral antigens
For virus-associated tumors, such as cervical cancer and a subset of head and neck cancers, epitopes derived from viral open reading frames contribute to the pool of neoantigens.
Tumor antigens can appear on the surface of the tumor in the form
of, for example, a mutated receptor, in which case they are recognized
by B cells.
For human tumors without a viral etiology, novel peptides (neo-epitopes) are created by tumor-specific DNA alterations.
Process
A large
fraction of human tumor mutations is effectively patient-specific.
Therefore, neoantigens may also be based on individual tumor genomes.
Deep-sequencing technologies can identify mutations within the
protein-coding part of the genome (the exome)
and predict potential neoantigens. In mice models, for all novel
protein sequences, potential MHC-binding peptides were predicted. The
resulting set of potential neoantigens was used to assess T cell
reactivity. Exome–based analyses were exploited in a clinical setting,
to assess reactivity in patients treated by either tumor-infiltrating lymphocyte
(TIL) cell therapy or checkpoint blockade. Neoantigen identification
was successful for multiple experimental model systems and human
malignancies.
The false-negative rate of cancer exome sequencing is low—i.e.:
the majority of neoantigens occur within exonic sequence with sufficient
coverage. However, the vast majority of mutations within expressed
genes do not produce neoantigens that are recognized by autologous T
cells.
As of 2015 mass spectrometry resolution is insufficient to
exclude many false positives from the pool of peptides that may be
presented by MHC molecules. Instead, algorithms are used to identify the
most likely candidates. These algorithms consider factors such as the
likelihood of proteasomal processing, transport into the endoplasmic reticulum, affinity for the relevant MHC class I alleles and gene expression or protein translation levels.
The majority of human neoantigens identified in unbiased screens
display a high predicted MHC binding affinity. Minor histocompatibility
antigens, a conceptually similar antigen class are also correctly
identified by MHC binding algorithms. Another potential filter examines
whether the mutation is expected to improve MHC binding. The nature of
the central TCR-exposed residues of MHC-bound peptides is associated
with peptide immunogenicity.
Nativity
A native antigen is an antigen that is not yet processed by an APC to smaller parts. T cells cannot bind native antigens, but require that they be processed by APCs, whereas B cells can be activated by native ones.
Antigenic specificity
Antigenic
specificity is the ability of the host cells to recognize an antigen
specifically as a unique molecular entity and distinguish it from
another with exquisite precision. Antigen specificity is due primarily
to the side-chain conformations of the antigen. It is measurable and
need not be linear or of a rate-limited step or equation. Both T cells and B cells are cellular components of adaptive immunity.
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