T cells are formed in bone marrow and mature in Thymus. How are they transported from bone marrow to thymus ? Through the lymph vessels ?
prothymocytes are attracted to the thymus from the Bone Marrow by a chemotaxis , thymotaxin, a factor from thymic epithelial cells. then it enters into the thymic cortex where Thy-1 and terminal deoxynucleotidyl transferase (TdT) is expressed. During TCR gene rearrangement, TdT increases TCR diversity by inserting nucleotides at the D and J junction sites. IL-2 and IL-2R are expressed leading to autocrine proliferation of T cells. now the pre-T cell rearranges TCR genes (gamma/delta, alpha/beta). At this stage the pre-T cells are CD3+CD4-CD8- or "double-negative" cells. Double-negative cells that productively rearrange gamma and delta chain gene segments develop into CD3+CD4-CD8- gamma/delta T cells that are exported to the periphery in small numbers. Successful rearrangement of a set of TCR genes suppresses further rearrangement of TCR genes on the sister chromatid , thus each cell only expresses TCR with a single specificity. The majority of double-negative cells will go on to rearrange alpha and beta chain gene segments. The beta chain genes are rearranged and expressed first with a pre-T alpha chain to form the pre-TCR . Once the pre-TCR recognizes some intrathymic ligand , a signal is transmitted through CD3 which: halts further beta chain gene rearrangement (allelic exclusion)enhances alpha chain gene rearrangement causes CD4 and CD8 to be expressed The alpha beta T cells now become CD4+CD8+ or "double-positive" cells. T cells which fail to productively rearrange TCR genes die by apoptosis.
At this point the T cells are in the deep cortex which contains epithelial cells expressing both class I and class II MHC molecules. T cells with alpha beta TCR which are capable of binding self-MHC on epithelial cells continue to proliferate and differentiate into CD4+CD8- or CD4-CD8+ T cells. Nonreactive (not self-MHC restricted) T cells die by apoptosis. Thus, T cells are positively selected for self-MHC restriction in the thymus.
T cells that survive positive selection traverse the junction between the cortex and medulla. Some of these T cells have low affinity TCR for self-MHC alone or combined with self-peptide while others have high affinity TCR. The medulla is rich in BM-derived dendritic cells and macrophages which express high levels of class I and class II MHC. T cells with high affinity TCR for self-MHC alone or combined with self-peptide interact with these dendritic cells and macrophages, and are eliminated by apoptosis. Thus, negative selection eliminates self-reactive T cells in the thymus.