Information AboutT Cell |
| CATEGORIES ABOUT T CELL | |
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T CELL SUBSETS Several different subsets of T cells have been described, each with a distinct function.
T CELL DEVELOPMENT IN THE THYMUS See Thymocyte for in-depth review of thymic selection All T cells originate from 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''', while the other 2% survive and leave the thymus to become mature immunocompetent T cells. Positive selection Double-positive Thymocytes move deep into the thymic 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 MHC molecules on the surface of cortical Epithelial cells. Only those Thymocytes which bind the MHC/antigen complex with adequate Affinity will receive a vital "survival signal." The other Thymocytes 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+ TH cell or a CD8+ TC 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 will become CD8+ cells. Negative selection 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 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 is 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 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 importantly 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 which act on PI(4,5)P2 on the inner leaflet of the membrane to create the active intermediaries di-acyl glycerol (DAG), inositol-1,4,5-trisphosphate (IP3) and phosphatidlyinositol-3,4,5-trisphosphate (PIP3). DAG binds and activates some PKCs, most importantly in T cells PKCθ , which is 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 notably IL-2 , a cytokine which promotes long term proliferation of activated T cells. SEE ALSO REFERENCES EXTERNAL LINKS
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