When the antigen is binds to TCR-CD3 complex then the T cell differentiation starts into the effectors and memory cells to activate the inflammatory response against the antigen. There are also some co-stimulatory signals that have role in T cell differentiation by which are being produced by the interaction of CD28 of T cells and B7. Then the thymus releases the CD4+ and CD8+ cells into the blood stream as a naïve cells during the G0 phase of cell cycle. These CD4+ and CD8+ are resting cells. Among the two naïve cells the CD8+ are less in number as compare to CD4+ but transcriptionally more active then CD4+. This less transcriptional activity may be due to the more condensed chromatine. These naïve cells may circulate in the blood stream and lymph nodes until they encounter a foreign particle. This is to and from circulation between blood stream and lymph node and the journey complete in 12-24 hours. The antigen encounter process in very specific and one T cell come across the antigen out of 105 cells.
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Figure1. T cell differentiation into repertoire memory and effectors cell
If any antigen get bounded to Major Histocompatibility Complex and this binding is recognized by the naïve T cells and get activated, then the cell cycle change from G0 phase to G1. It was a hypothesis earlier that this T cell activation is trigger by the antigen and TCR-CD3 complex interaction along with CD28 and B7 on Antigen presenting cell's co-stimulatory effect. The transcription of IL-2 and IL-2R gene induce by this T cell activation and the IL-2 synthesis increased about 100 fold during T cell activation. In return these IL-2 get attached with the IL-2 receptors and activate the naïve T cell to differentiation and proliferation of memory and effecter cells. The effectors cells have the cytotoxic activity and cytokine synthesis as B cells. The effectors cells has very small life span and possesses the ability to express the cell surface molecules. On the basis of nature of cytokines secreted by the effectors cells can be divided into the two subset of population. One is the THI subset secrete IL-2, INF- γ and TNF-β. These TH1 cells has the cell mediated ability of cytotoxic T cell activation and delayed hypersensitivity. Other population is TH2 cells that secrete the IL-4, IL-5, IL-6 and IL-10.
The memory cells derived from the T cell differentiation mainly from naïve T cell and also from the effectors T cell. The memory cells react quickly if the antigen encountered is the previously encountered antigen. These memory cells have long life span. The memory cells remain in resting stage if there is no any antigen in action. The memory cells are derived form the macrophages and dendritic cells in contrast to naïve T cells which are derived from the dendritic cells only. There is very high transcriptional expression of T cell adhesion molecules that enable the wide range of antigen to adhere antigen presenting cells.
Thymus selection of T cell
There are numerous T cell repertoires due to the DNA re-arrangements which have different αβ, γδ receptors. The gene that are encoded in T cell receptor supposed to recognized by the soluble antigen, that can be foreign antigen and that also can be self antigen, and self MHC antigen, but not the foreign MHC self antigen. The T cell has the ability to come across the self MHC foreign antigen. To do this the thymus must possess two selection pathways for selection of particular antigen. These selection pathways are
Positive selection is for those thymocytes that have self MHC molecule receptors, and make the restricted to MHC only. The cells that are not attached will be eliminated by the process of apoptosis in thymus. The positive selection is being done in the cortex of thymus and the epithelial cells of thymus present the MHC to T cells which are immature having double positive CD8+ and CD4. The gene re-arrangements is carried out by the RAG 1 and 2 in T cells which is mature with the TdT protein. These immature thymocytes possess β chain and let the RAG 1 and RAG 2 for the gene re-arrangements. The T cell after the re-arrangement has the ability of self MHC recognitions. The self MHC only allows the binding of αβ chain present on T cell for survival. The T cells having αβ heterodimer will be unsuccessful to recognized and ultimately undergo apoptosis within 3 to 4 days.
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Figure2. Positive selection
Negative selection is carried out to eliminate the thymocytes which have high affinity to self MHC molecules and finally results in cell's self tolerance. The negative selection make it sure that those cells which possess high affinity against the self MHC or self antigen to be killed by the process of apoptosis.
The cells with low affinity will be survived. Afterword the cells experience negative selection by coming across the thymus stromal cells. During the negative cells the dendritic and macrophages (antigen presenting cells) offer the self antigen on class1 and class 2 MHC interact with T cell which is under development.
Figure3. Negative Selection
During the positive selection in which self MHC molecules are selected and this selection lead to their survival and in negative selection the cells which have high affinity for self antigen will be abolished. If it is so then there would not be any T cell left, but many other factors has their effects and drive the MHC for positive and negative selection and abolish the cells not required.