T cell

T cells belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocyte types, such as B cells and natural killer cells 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.Several different subsets of T cells have been described, each with a distinct function.
*Helper T cells (effector T cells or T_h cells) are the "middlemen" of the adaptive immune system. Once activated, they divide rapidly and secrete small proteins called cytokines that regulate or "help" the immune response. Depending on the cytokine signals received, these cells differentiate into T_H1, T_H2, T_H3, T_H17,T_HF, or one of other subsets, which secrete different cytokines. CD4+ cells associated with MHC class II.

*Cytotoxic T cells (T_C cells, or CTLs) destroy virally infected cells and tumor cells, and are also implicated in transplant rejection. These cells are also known as CD8⁺ T cells (associated with MHC class I), since they express the CD8 glycoprotein at their surface. Through SLOBclarifyme|date=September 2008|reason=was linked to unrelated topic SLOB; valid term or vandalism? interaction with helper T cells, these cells can be transformed into regulatory T cells, which prevent autoimmune diseases such as experimental autoimmune encephalomyelitis. [cite web|url=http://www.jci.org/cgi/content/full/114/9/1198|title=An integrated view of suppressor T cell subsets in immunoregulation]

*Memory T cells 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_CM cells) and effector memory T cells (T_EM cells). Memory cells may be either CD4+ or CD8+.

*Regulatory T cells (T_reg 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_reg cells and the adaptive T_reg cells. Naturally occurring T_reg cells (also known as CD4⁺CD25⁺FoxP3⁺ T_reg cells) arise in the thymus, whereas the adaptive T_reg cells (also known as Tr1 cells or Th3 cells) may originate during a normal immune response. Naturally occurring T_reg 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 cells (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_h and T_c cells (i.e., cytokine production and release of cytolytic/cell killing molecules).

*γδ T cells represent a small subset of T cells that possess a distinct TCR on their surface. A majority of T cells have a 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 lymphocytes (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

See Thymocyte for in-depth review of thymic selection.

All T cells originate from hematopoietic stem cells in the bone marrow. Hematopoietic progenitors derived from hematopoietic stem cells populate the thymus and expand by cell division to generate a large population of immature thymocytes. [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] ] The earliest thymocytes express neither CD4 nor CD8, and are therefore classed as "double-negative" (CD4^-CD8^-) cells. As they progress through their development they become "double-positive" thymocytes (CD4⁺CD8⁺), and finally mature to "single-positive" (CD4⁺CD8^- or CD4^-CD8⁺) 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 thymocytes move deep into the thymic cortex where they are presented with self-antigens (i.e., antigens that are derived from molecules belonging to the host of the T cell) complexed with 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 macrophages. This process is called "positive selection".

Whether a thymocyte becomes a CD4+ cell or a CD8+ cell is also determined during positive selection. Double-negative 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 in the passage 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 cells (APCs) such as dendritic cells and macrophages. 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 cells. 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 activation

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 family members on the 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 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 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 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.

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, Trim, 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 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 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.

ee also

* Apoptosis
* Naive T cell
* Memory T cell
* γδ T cell

References

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]