T cell

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T 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
SystemImmune system
Identifiers
Latinlymphocytus T
MeSHD013601
THH2.00.04.1.02007
FMA62870
Anatomical terms of microanatomy

T cells are one of the important types of

lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface
.

T cells are born from

hematopoietic stem cells,[1] found in the bone marrow. Developing T cells then migrate to the thymus gland to develop (or mature). T cells derive their name from the thymus.[2][3] 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" (cytotoxic) 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 signalling 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, the CD4+ helper T (TH) cells function by further activating memory B cells and cytotoxic T cells, which leads to a larger immune response. The specific adaptive immune response regulated by the TH cell depends on its subtype (such as T-helper1, T-helper2, T-helper17, regulatory T-cell),[4] which is distinguished by the types of cytokines they secrete.[2]

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+

lymphoid cells. The process of differentiation then proceeds to a common lymphoid progenitor (CLP), which can only differentiate into T, B or NK cells.[5] These CLP cells then migrate via the blood to the thymus, where they engraft:. Henceforth they are known as thymocytes
, the immature stage of a T cell.

The earliest cells which arrived in the thymus are commonly termed double-negative, as they express neither the

downregulate
c-kit and are termed double-negative one (DN1) cells. To become T cells, the thymocytes must undergo multiple DN stages as well as positive selection and negative selection.

Double negative thymocytes can be identified by the surface expression of CD2, CD5 and CD7. Still during the double negative stages, CD34 expression stops and CD1 is expressed. Expression of both CD4 and CD8 makes them double positive, and matures into either CD4+ or CD8+ 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. This process is essential in developing immunity to threats that the immune system has not encountered before, since due to random variation there will always be at least one TCR to match any new pathogen.

A thymocyte can only become an active T cell when it survives the process of developing a functional TCR. 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 due to this huge variety they must be tested to make sure they work at all. First, the thymocytes 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, the cells then must test if their TCR will identify threats correctly, and to do this it is required to recognize the body’s major histocompatibility complex (MHC) in a process known as positive selection. The thymocyte must also ensure that it does not react adversely to "self" antigens, called negative selection. If both positive and negative selection are successful, the TCR becomes fully operational and the thymocyte becomes a T cell.

TCR β-chain 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 recombination and constant region genes in an attempt to create a functional TCRβ chain. As the developing thymocyte progresses through to the DN3 stage (CD44CD25+), the thymocyte 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 silence the alternate allele).[7] Although these signals require the pre-TCR at the cell surface, they are independent of ligand binding to the pre-TCR. If the chains successfully pair a pre-TCR forms, and the cell downregulates CD25 and is termed a DN4 cell (CD25CD44). These cells then undergo a round of proliferation, and begin to re-arrange the TCRα locus during the double-positive stage.

Positive selection

The process of positive selection takes 3 to 4 days and occurs in the thymic cortex.[8] 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, which reside on the surface of cortical epithelial cells. Only thymocytes that interact well with MHC-I or MHC-II will receive a vital "survival signal", while those that cannot interact strongly enough will receive no signal and die from neglect. This process ensures that the surviving thymocytes will have an 'MHC affinity' that means they can serve useful functions in the body, responding to MHC molecules to assist immune responses. The vast majority of developing thymocytes will not pass positive selection, and die during this process.[9]

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+ "helper" cells, whereas thymocytes that interact well with MHC class I molecules mature into CD8+ "killer" cells. A thymocyte 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+, both CD8+ and CD4+ cells are now single positive cells.[10]

This process does not filter for thymocytes that may cause autoimmunity. The potentially autoimmune cells are removed by the following process of negative selection, which occurs in the thymic medulla.

Negative selection

Negative selection removes thymocytes that are capable of strongly binding with "self" MHC molecules. 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

Treg cells. The remaining cells exit the thymus as mature naive T cells, also known as recent thymic emigrants.[12] 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.

TCR development summary

β-selection is the first checkpoint, where thymocytes 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 thymocytes have successfully rearranged their TCRα locus and are capable of recognizing MHC molecules with appropriate affinity. Negative selection in the medulla then eliminates thymocytes that bind too strongly to self-antigens expressed on MHC molecules. These selection processes allow for tolerance of self by the immune system. Typical naive 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.[13] The thymus contributes fewer cells as a person ages. As the thymus shrinks by about 3%[14] 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.

Conventional adaptive T cells

Helper CD4+ T cells

Depiction of the various key subsets of CD4-positive T cells with corresponding associated cytokines and transcription factors.

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.[15]

CD4+ Helper T cell subsets
Cell type Cytokines Produced Key Transcription Factor Role in immune defense Related diseases
Th1
IFNγ
, IL-2
Tbet Produce an inflammatory response, key for defense against intracellular bacteria, viruses and cancer. MS, Type 1 diabetes
Th2
IL-4, IL-5, IL-13 GATA-3 Immunologically important against extracellular pathogens, such as worm infections Asthma and other allergic diseases
Th17
IL-17F, IL-17A, IL-22 RORγt Defense against gut pathogens and at mucosal barriers MS, Rheumatoid Arthritis, Psoriasis
Th9[16][17] IL-9 IRF4, PU.1 Defense against helminths (parasitic worms) and cell-dependent allergic inflammation Multiple Sclerosis
Tfh IL-21, IL-4 Bcl-6 Help B cells produce antibodies Asthma and other allergic diseases
Th22[18][17] IL-22 AHR Pathogenesis of allergic airway diseases and predominantly anti-inflammatory Crohn's Disease, Rheumatoid Arthritis, Tumors

Cytotoxic CD8+ T cells

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

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

Antigen-naive T cells expand and differentiate into memory and

CD45RO.[20]

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.[21] TEMRA stands for terminally differentiated effector memory cells re-expressing CD45RA, which is a marker usually found on naive T cells.[22]
  • 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.[23]
  • Virtual memory T cells (TVM) 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,[24] it is now known that CD4 virtual memory cells also exist.[25]

Regulatory CD4+ T cells

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.

IPEX
.

Several other types of T cells have suppressive activity, but do not express FOXP3 constitutively. These include

Th17 cells have been added to this list.[27]

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.[28] Furthermore, these T cell subsets are being translated into many therapies against malignancies such as leukemia, for example.[29]

Natural killer T cell

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.[30]

Mucosal associated invariant T cells

Mucosal associated invariant T (MAIT) cells display

MR1, is responsible for presenting bacterially-produced vitamin B metabolites to MAIT cells.[33][34][35] After the presentation of foreign antigen by MR1, MAIT cells secrete pro-inflammatory cytokines and are capable of lysing bacterially-infected cells.[31][35] MAIT cells can also be activated through MR1-independent signaling.[35] In addition to possessing innate-like functions, this T cell subset supports the adaptive immune response and has a memory-like phenotype.[31] Furthermore, MAIT cells are thought to play a role in autoimmune diseases, such as multiple sclerosis, arthritis and inflammatory bowel disease,[36][37] although definitive evidence is yet to be published.[38][39][40][41]

Gamma delta T cells

aminobisphosphonates
, which upregulate endogenous IPP/DMAPP.

Activation

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.[42]

Activation of CD4+ T cells occurs through the simultaneous engagement of the

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.[43] 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.[44][45][46]

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,[47] 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

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.[48]

The

, which allows the aggregation of signalling complexes around these proteins.

Phosphorylated

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

CARD (Caspase activation and recruitment domains) domains; that then binds TRAF6, which is ubiquitinated at K63.: 513–523 [49] 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.[50] 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.[49]

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.[51]

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".[52]

T cell activation is modulated by reactive oxygen species.[53]

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.[54] 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.[54][55]

Clinical significance

Deficiency

Causes of

ataxia-telangiectasia (AT) and Wiskott–Aldrich syndrome (WAS).[56]

The main pathogens of concern in T cell deficiencies are

fungal infections are also more common and severe in T cell deficiencies.[57]

Cancer

Cancer of T cells is termed T-cell lymphoma, and accounts for perhaps one in ten cases of non-Hodgkin lymphoma.[58] The main forms of T cell lymphoma are:

Exhaustion

T cell exhaustion is a poorly defined or ambiguous term.[59][60] There are three approaches to its definition.[59] "The first approach primarily defines as exhausted the cells that present the same cellular dysfunction (typically, the absence of an expected effector response). The second approach primarily defines as exhausted the cells that are produced by a given cause (typically, but not necessarily, chronic exposure to an antigen). Finally, the third approach primarily defines as exhausted the cells that present the same molecular markers (typically, programmed cell death protein 1 [PD-1])."[59]

Dysfunctional T cells are characterized by progressive loss of function, changes in transcriptional profiles and sustained expression of inhibitory receptors. At first, cells lose their ability to produce

TNFα, which is followed by the loss of high proliferative capacity and cytotoxic potential, and eventually leads 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.[61] Exhausted T cells preserve their functional exhaustion even after repeated antigen exposure.[62]

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.

lymphocyte activation gene 3 protein (LAG3).[65][66] Soluble molecules such as cytokines IL-10 or TGF-β are also able to trigger exhaustion.[67][68] 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.[69] Furthermore, T cell exhaustion is reverted after depletion of Treg cells and blockade of PD1.[70] 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.[71][72] Currently there are studies aiming to utilize inhibitory receptor blockades in treatment of sepsis.[73][74][75]

During transplantation

While during infection T cell exhaustion can develop following persistent antigen exposure after graft transplant similar situation arises with alloantigen presence.[76] It was shown that T cell response diminishes over time after kidney transplant.[77] These data suggest T cell exhaustion plays an important role in tolerance of a graft mainly by depletion of alloreactive CD8 T cells.[72][78] Several studies showed positive effect of chronic infection on graft acceptance and its long-term survival mediated partly by T cell exhaustion.[79][80][81] It was also shown that recipient T cell exhaustion provides sufficient conditions for NK cell transfer.[82] 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.[83]

During cancer

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.[84][85][86] T cell exhaustion can also play a role in cancer relapses as was shown on leukemia.[87] 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.[88] 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.[89] Inhibitory receptors targeted by those medical procedures are vital in T cell exhaustion and blocking them can reverse these changes.[90]

See also

References

  1. ^ "5. Hematopoietic Stem Cells". Stem Cell Information. Bethesda, MD: National Institutes of Health, U.S. Department of Health and Human Services. 17 June 2001. Archived from the original on 29 October 2016. Retrieved 21 December 2021.
  2. ^ a b Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002). "Helper T Cells and Lymphocyte Activation". Molecular Biology of the Cell (4th ed.). Garland Science.
  3. ^ Alberts B, Johnson A, Lewis J, Raff M, Roberts K, Walter P (2002). "Helper t Cells and Lymphocyte Activation". Molecular Biology of the Cell (4th ed.). Garland Science. p. 1367. T cells ... derive their [name] from the organs in which they develop. T cells develop [mature] in the thymus
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Further reading

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