T cell
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2008-07-07T13:29:54Z
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'''T cells''' belong to a group of [[white blood cell]]s known as [[lymphocytes]], and play a central role in [[cell-mediated immunity]]. They can be distinguished from other lymphocyte types, such as [[B cell]]s and [[natural killer cell]]s by the presence of a special receptor on their cell surface called the ''[[T cell receptor]]'' (TCR). The abbreviation ''T'', in ''T cell'', stands for [[thymus]], since it is the principal organ in the T cell's development.
==T cell subsets==
[[Image:TCR-MHC bindings.png|thumb|250px|Molecular association of CD8+ T cells with MHC class I and CD4+ T cells with MHC class II]]
Several different subsets of T cells have been described, each with a distinct function.
*'''[[Helper T cell]]s''' ('''effector T cells''' or '''T<sub>h</sub> cells''') are the "middlemen" of the [[adaptive immune system]]. Once activated, they divide rapidly and secrete small proteins called [[cytokine]]s that regulate or "help" the immune response. Depending on the cytokine signals received, these cells differentiate into [[Th1|T<sub>H</sub>1]], [[Th2|T<sub>H</sub>2]], [[Th17|T<sub>H</sub>17]], or one of other subsets, which secrete different cytokines. [[CD4+]] cells associated with [[MHC class II]].
*'''[[Cytotoxic T cell]]s''' (T<sub>C</sub> cells, or CTLs) destroy virally infected cells and tumor cells, and are also implicated in [[Organ transplant|transplant]] rejection. These cells are also known as CD8<sup>+</sup> T cells (associated with MHC class I), since they express the [[CD8]] glycoprotein at their surface. Through [[SLOB]] interaction with [[helper T cell]]s, these cells can be transformed into [[regulatory T cell]]s, which prevent [[autoimmune]] diseases such as [[experimental autoimmune encephalomyelitis]].<ref>{{cite web|url=http://www.jci.org/cgi/content/full/114/9/1198|title=An integrated view of suppressor T cell subsets in immunoregulation}}</ref>
*'''[[Memory T cell]]s''' are a subset of [[antigen]]-specific T cells that persist long-term after an infection has resolved. They quickly expand to large numbers of effector T cells upon re-exposure to their cognate antigen, thus providing the immune system with "memory" against past infections. Memory T cells comprise two subtypes: central memory T cells (T<sub>CM</sub> cells) and effector memory T cells (T<sub>EM</sub> cells). Memory cells may be either CD4+ or CD8+.
*'''[[Regulatory T cell]]s''' (T<sub>reg</sub> cells), formerly known as '''suppressor 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 auto-reactive T cells that escaped the process of negative selection in the thymus. Two major classes of CD4+ regulatory T cells have been described, including the naturally occurring T<sub>reg</sub> cells and the adaptive T<sub>reg</sub> cells. Naturally occurring T<sub>reg</sub> cells (also known as CD4<sup>+</sup>CD25<sup>+</sup>FoxP3<sup>+</sup> T<sub>reg</sub> cells) arise in the [[thymus]], whereas the adaptive T<sub>reg</sub> cells (also known as Tr1 cells or Th3 cells) may originate during a normal immune response. Naturally occurring T<sub>reg</sub> cells can be distinguished from other T cells by the presence of an intracellular molecule called [[FoxP3]]. Mutations of the ''FOXP3'' gene can prevent regulatory T cell development, causing the fatal [[autoimmune disease]] [[IPEX]].
*'''[[Natural killer T cell]]s''' (NKT cells) are a special kind of lymphocyte that bridges the [[adaptive immune system]] with the [[innate immune system]]. Unlike conventional T cells that recognize peptide antigen presented by [[major histocompatibility complex]] (MHC) molecules, NKT cells recognize glycolipid antigen presented by a molecule called CD1d. Once activated, these cells can perform functions ascribed to both T<sub>h</sub> and T<sub>c</sub> cells (i.e., cytokine production and release of cytolytic/cell killing molecules).
*'''[[γδ T cell]]s''' represent a small subset of T cells that possess a distinct [[T cell receptor|TCR]] on their surface. A majority of T cells have a [[T cell receptor|TCR]] composed of two [[glycoprotein]] chains called α- and β- TCR chains. However, in γδ T cells, the TCR is made up of one γ-chain and one δ-chain. This group of T cells is much less common (5% of total T cells) than the αβ T cells, but are found at their highest abundance in the gut [[mucosa]], within a population of lymphocytes known as [[intraepithelial lymphocyte]]s (IELs). The antigenic molecules that activate γδ T cells are still widely unknown. However, γδ T cells are not MHC restricted and seem to be able to recognise whole proteins rather than requiring peptides to be presented by MHC molecules on antigen presenting cells. Some recognize MHC class IB molecules though. Human Vγ9/Vδ2 T cells, which constitute the major γδ T cell population in peripheral blood, are unique in that they specifically and rapidly respond to a small non-peptidic microbial metabolite, [[HMB-PP]], an [[isopentenyl pyrophosphate]] precursor.
==T cell development in the thymus==<!-- This section is linked from [[apoptosis]] -->
See [[Thymocyte]] for in-depth review of thymic selection
All T cells originate from [[pluripotential hemopoietic stem cell|hematopoietic stem cells]] in the [[bone marrow]]. Hematopoietic progenitors derived from [[pluripotential hemopoietic stem cell|hematopoietic stem cells]] populate the [[thymus]] and expand by cell division to generate a large population of immature [[thymocytes]].<ref>Schwarz BA, Bhandoola A. Trafficking from the bone marrow to the thymus: a prerequisite for thymopoiesis. ''Immunol Rev'' 209:47, 2006. [http://www.blackwell-synergy.com/doi/abs/10.1111/j.0105-2896.2006.00350.x full text]</ref> The earliest [[thymocytes]] express neither CD4 nor CD8, and are therefore classed as ''double-negative'' (CD4<sup>-</sup>CD8<sup>-</sup>) cells. As they progress through their development they become ''double-positive'' thymocytes (CD4<sup>+</sup>CD8<sup>+</sup>), and finally mature to ''single-positive'' (CD4<sup>+</sup>CD8<sup>-</sup> or CD4<sup>-</sup>CD8<sup>+</sup>) thymocytes that are then released from the [[thymus]] to peripheral tissues.
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.
===Positive selection===
Positive selection ''selects for'' T-cells capable of interacting with MHC.
Double-positive [[thymocyte]]s move deep into the thymic [[cortex (anatomy)|cortex]] where they are presented with self-[[antigen]]s (i.e., antigens that are derived from molecules belonging to the host of the T cell) complexed with [[major histocompatibility complex|MHC]] molecules on the surface of cortical [[epithelial]] cells. Only those thymocytes that bind the MHC/antigen complex with adequate [[affinity]] will receive a vital "survival signal." Developing thymocytes that do not have adequate affinity cannot serve useful functions in the body; the cells must be able to interact with MHC and peptide complexes in order to affect immune responses. Therefore, the other [[thymocytes]] with low affinity die by [[apoptosis]] (programmed cell death), and their remains are engulfed by [[macrophage]]s. This process is called ''positive selection''.
Whether a thymocyte becomes a CD4+ cell or a CD8+ cell is also determined during positive selection. Double-positive cells that are positively selected on MHC class II molecules will become CD4+ cells, and cells positively selected on MHC class I molecules become CD8+ cells.
Note that this process does not remove from the population thymocytes that would cause [[autoimmunity]] or a reaction with one's own cells. The removal of such cells is dealt with by negative selection, which is discussed below.
===Negative selection===
Negative selection ''selects against'' cells reacting against self peptides presented by MHC.
[[Thymocytes]] that survive positive selection migrate towards the boundary of the thymic cortex and thymic [[medulla]]. While in the medulla, they are again presented with self-antigen in complex with MHC molecules on [[antigen-presenting cell]]s (APCs) such as [[dendritic cell]]s and [[macrophage]]s. Thymocytes that interact too strongly with the antigen receive an [[apoptosis]] signal that causes their death; the vast majority of all thymocytes initially produced end up dying during thymic selection. A small minority of the surviving cells are selected to become [[regulatory T cell]]s. The remaining cells will then exit the thymus as mature [[naive T cells]]. This process is called ''negative selection'', an important mechanism of [[immunological tolerance]] that prevents the formation of self-reactive T cells capable of generating [[autoimmune disease]] in the host.
====T cell maturation paradox====
Positive and negative selection should theoretically kill all developing T cells. The first stage of selection kills all T cells that do not interact with self-MHC, while the second stage selection kills all cells that do. This poses the question: How do we have immunity at all? Currently, two models attempt to explain this:
#[[Differential Avidity Hypothesis]] - States that the strength of signal dictates the fate of the T cell.
#[[Differential Signaling Hypothesis]]- States that signals transduced differ at each stage.
==T cell maturation==
Maturation of T Cells occurs in the thymus. The first step is the rearrangement of the variable, joining, and constant region genes of the chain of the T cell antigen receptor in a way very similar to that of heavy chain rearrangement needed for immunoglobulin synthesis. In fact, the same enzymes are used for both.
Production of a functional TCR chain, signals expression of both CD4 and CD8 on the cell surface. This induces the genetic rearrangements needed to produce a functional TCR chain and an increase in TCR membrane expression. CD3 is then expressed, which produces a functional TCR complex (to be described later).
At this point, some of the T cells stop making CD8, so only CD4 remains on their cell membrane. The others undergo the reverse process, so they express only CD8. T cells then learn to not attack self tissues and to respond to antigen only if it is associated with a self histocompatibility antigen. This requires two steps:
*First, the immature, but CD4 or CD8 positive T cells are exposed to cells in the thymus, which have class I and class II histocompatibility antigens on them. T cells which are able to bind to one or the other of these antigens are protected, whereas the others die.
*Second, the cells that survive the above selection process are exposed to self antigens that have been taken up and associated with either class I or class II MHC antigen. Those that bind at this stage die by apoptosis.
The cells that survive are those that recognize non-self antigens associated with MHC antigens. After a little more maturation, they exit the thymus to perform their role in immune responses.
==T cell activation==
[[Image:T cell activation.png|250px|right]]
Although the specific mechanisms of activation vary slightly between different types of T cells, the "two-signal model" in CD4+ T cells holds true for most. Activation of CD4+ T cells occurs through the engagement of both the [[T cell receptor]] and [[CD28]] on the T cell by the [[Major histocompatibility complex]] [[peptide]] and [[B7 (protein)|B7]] family members on the [[antigen-presenting cell|APC]], respectively. Both are required for production of an effective immune response; in the absence of CD28 [[co-stimulation]], T cell receptor signalling alone results in [[anergy]]. The signalling pathways downstream from both [[CD28]] and the T cell receptor involve many proteins.
The first signal is provided by binding of the T cell receptor to a short peptide presented by the major histocompatibility complex (MHC) on another cell. This ensures that only a T cell with a TCR specific to that peptide is activated. The partner cell is usually a professional antigen presenting cell (APC), usually a [[dendritic cell]] in the case of [[naive T cell|naïve]] responses, although B cells and macrophages can be important APCs. The peptides presented to [[CD8]]+ T cells by MHC class I molecules are 8-9 amino acids in length; the peptides presented to [[CD4]]+ cells by [[MHC]] class II molecules are longer, 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 [[necrosis|necrotic]]-bodies or [[heat-shock proteins]]. The only co-stimulatory receptor expressed constitutively by naïve T cells is [[CD28]], so co-stimulation for these cells comes from the [[CD80]] and [[CD86]] proteins on the APC. Other receptors are expressed upon activation of the T cell, such as [[OX40]] and [[CD278|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 [[anergy|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.
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 (immunology)|CD3]] proteins: CD3εγ and CD3εδ heterodimers and, most important, a CD3ζ homodimer, which has a total of six [[immunoreceptor tyrosine-based activation motif|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]], [[Trim]], [[LAT]] and [[SLP-76]], which allows the aggregation of signalling complexes around these proteins.
Phosphorylated [[linker of activated T cells|LAT]] recruits [[SLP-76]] to the membrane, where it can then bring in [[PLCγ]], [[VAV1]], [[Itk]] and potentially [[PI3K]]. Both [[PLCγ]] and [[PI3K]] act on PI(4,5)P2 on the inner leaflet of the membrane to create the active intermediaries diacylglycerol ([[DAG]]), inositol-1,4,5-trisphosphate ([[IP3]]), and phosphatidlyinositol-3,4,5-trisphosphate ([[PIP3]]). DAG binds and activates some PKCs, most important, in T cells [[PKCθ]], a process important for activating the transcription factors [[NF-κB]] and AP-1. [[IP3]] is released from the membrane by [[PLCγ]] and diffuses rapidly to activate receptors on the [[endoplasmic reticulum|ER]], which induce the release of [[calcium]]. The released calcium then activates [[calcineurin]], and [[calcineurin]] activates [[NFAT]], which then translocates to the nucleus. NFAT is a [[transcription factor]], which activates the transcription of a pleiotropic set of genes, most notable, [[IL-2]], a cytokine that promotes long term proliferation of activated T cells.
==See also==
* [[Apoptosis]]
* [[Naive T cell]]
* [[Memory T cell]]
* [[γδ T cell]]
==References==
{{reflist}}
==External links==
* [http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=imm.TOC&depth=2 Immunobiology, 5th Edition]
* [http://www.niaid.nih.gov/publications/immune/the_immune_system.pdf niaid.nih.gov] – The Immune System
* [http://www.tcells.org T-cell Group - Cardiff University]
* [http://content.nejm.org/cgi/content/full/358/25/2698 (Successful!) Treatment of Metastatic Melanoma with Autologous CD4+ T Cells against NY-ESO-1]
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