T cell
T cell | |
---|---|
Details | |
System | Immune system |
Identifiers | |
Latin | lymphocytus T |
MeSH | D013601 |
TH | H2.00.04.1.02007 |
FMA | 62870 |
Anatomical terms of microanatomy |
T cells are one of the important types of
T cells are born from
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]
Development
Origin, early development and migration to the thymus
All T cells originate from c-kit+Sca1+
The earliest cells which arrived in the thymus are commonly termed double-negative, as they express neither the
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 (CD44−CD25+), 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 (CD25−CD44−). 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
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
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
Memory T cells
Antigen-naive T cells expand and differentiate into memory and
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
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.
Several other types of T cells have suppressive activity, but do not express FOXP3 constitutively. These include
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
Mucosal associated invariant T cells
Mucosal associated invariant T (MAIT) cells display
Gamma delta T cells
Activation
Activation of CD4+ T cells occurs through the simultaneous engagement of the
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
The
Phosphorylated
PLC-γ can also initiate the
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 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
The main pathogens of concern in T cell deficiencies are
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:
- Extranodal T cell lymphoma
- Sézary syndrome and Mycosis fungoides
- Anaplastic large cell lymphoma
- Angioimmunoblastic T cell lymphoma
Exhaustion
It has been suggested that this section be T cell exhaustion. (Discuss ) (May 2023) |
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
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.
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
- Chimeric antigen receptor T cell
- Gut-specific homing
- Immunoblast
- Immunosenescence
- Parafollicular cell also called C cell
References
- ^ "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.
- ^ 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.
- ^ 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
- PMID 22474485.
- PMID 28002722.
- PMID 17325202.
- ISBN 9780815342434.
- PMID 24927565.
- PMID 12414722.
- S2CID 15983629.
- S2CID 33154019.
- PMID 28814669.
- ISBN 9780815342434.
- PMID 10837068.
- PMID 17476341.
- PMID 32973809.
- ^ PMID 30867582.
- PMID 25261209.
- S2CID 4378970.
- S2CID 22340282.
- S2CID 16412760.
- PMID 18657274.
- PMID 23947354.
- PMID 21288770.
- PMID 27894837.
- S2CID 11294516.
- PMID 24434314.
- S2CID 30992456.
- PMID 33506055.
- PMID 17353286.
- ^ PMID 26217338.
- PMID 21458588.
- PMID 26468291.
- PMID 25339949.
- ^ PMID 26136743.
- PMID 26778581.
- PMID 28119072.
- PMID 24450998.
- PMID 19416870.
- S2CID 27717815.
- S2CID 4419703.
- NIAID resource booklet "Understanding the Immune System (pdf)".
- PMID 17129182.
- S2CID 574770.
- S2CID 38040377.
- PMID 15300249.
- ^ Jennifer Rolland and Robyn O'Hehir, "Turning off the T cells: Peptides for treatment of allergic Diseases," Today's life science publishing, 1999, Page 32
- PMID 25578468.
- ^ ISBN 978-0-12-289632-3.
- S2CID 28521713.
- PMID 21045195.
- ^ Graham W (2014-04-14). "SpaceX ready for CRS-3 Dragon launch and new milestones". NASAspaceflight.com. Retrieved 2014-04-14.
- PMID 26471060.
- ^ PMID 17825415.
- PMID 24636916.
- ^ a b T-Cell Disorders at eMedicine
- ^ ISBN 978-1-4051-2665-6.
- ^ "The Lymphomas" (PDF). The Leukemia & Lymphoma Society. May 2006. p. 2. Retrieved 2008-04-07.
- ^ PMID 34555119.
- PMID 31570879.
- PMID 20201977.
- PMID 29483916.
- PMID 7966595.
- PMID 22623779.
- S2CID 11052693.
- PMID 29914540.
- PMID 17041596.
- PMID 19604493.
- PMID 23947355.
- PMID 25113973.
- PMID 21798063.
- ^ PMID 22187279.
- PMID 27993215.
- PMID 27671246.
- S2CID 21657071.
- PMID 11375065.
- PMID 25377077.
- S2CID 33409478.
- PMID 26170387.
- PMID 26963287.
- S2CID 5348557.
- PMID 29197679.
- PMID 22186141.
- PMID 27809856.
- PMID 29507342.
- PMID 22189042.
- PMID 29477343.
- PMID 26230954.
- ^ "U.S. FDA Approved Immune-Checkpoint Inhibitors and Immunotherapies". Medical Writer Agency | 香港醫學作家 | MediPR | MediPaper Hong Kong. 2018-08-21. Retrieved 2018-09-22.
- PMID 21576466.
Further reading
- Janeway Jr CA, Travers P, Walport M, Shlomchik MJ (2001). Immunobiology 5 : the immune system in health and disease (5th ed.). New York: Garland Science. ISBN 978-0-8153-3642-6.
- "The Immune System" (PDF). National Institute of Allergy and Infectious Diseases. September 2003. Archived from the original (PDF) on 25 June 2009.