* B and T lymphocytes arise from a common bone marrow-derived precursor that becomes committed to the lymphocyte lineage. B cell maturation proceeds in the bone marrow, whereas early T cell progenitors migrate to and complete their maturation in the thymus. Early maturation is characterized by cell proliferation induced by cytokines, mainly IL-7, leading to an expansion in the numbers of lymphocytes that have just committed to individual lineages.
* Extracellular signals induce the activation of transcription factors that induce the expression of lineage-specific genes and open up specific antigen receptor gene loci at the level of chromatin accessibility.
* B and T cell development involves the somatic rearrangement of antigen receptor gene segments and the initial expression of the Ig heavy chain | protein in B cell precursors and TCR P molecules in T cell precursors. The initial expression of pre-antigen receptors and the subsequent expression of antigen receptors are essential for the survival, expansion, and maturation of developing lymphocytes and for selection processes that lead to a diverse repertoire of useful antigen specificities.
* The antigen receptors of B and T cells are encoded by receptor genes made up of a limited number of gene segments that are spatially segregated in the germline antigen receptor loci but are somatically recombined in developing B and T cells.
* Separate loci encode the Ig heavy chain, Ig k light chain, Ig X light chain, TCR P chain, TCR a and 8 chains, and TCR y chain. These loci contain V, J, and, in the Ig heavy chain and TCR P and 8 loci only, D gene segments. The J segments lie immediately upstream of exons encoding constant domains, and V segments lie a large distance upstream of the J segments. When present, D segments lie between the V and J clusters. Somatic rearrangement of both Ig and TCR loci involves the joining of D and J segments in the loci that contain D segments, followed by the joining of the V segment to the recombined DJ segments in these loci or direct V-to-J joining in the other loci.
* This process of somatic gene recombination is mediated by a recombinase enzyme complex that includes the lymphocyte-specific components Rag-1 and Rag-2.
* The diversity of the antibody and TCR repertoires is generated by the combinatorial associations of multiple germline V, D, and J genes and junctional diversity generated by the addition or removal of random nucleotides at the sites of recombination. These mechanisms generate the most diversity at the junctions of the segments that form the third hypervariable regions of both antibody and TCR polypeptides.
* B cell maturation occurs in stages characterized by different patterns of Ig gene rearrangement and expression. In the earliest B cell precursors, called pro-B cells, Ig genes are initially in the germline configuration, and D to J rearrangement occurs at the Ig heavy chain locus.
* At the pro-B to pre-B cell transition, V-D-J recombination is completed at the Ig H chain locus. A primary RNA transcript containing the VDJ exon and Ig C gene exons is produced, and the VDJ exon is spliced to the | C region exons of the heavy chain RNA to generate a mature mRNA that is translated into the | heavy chain protein. The pre-BCR is formed by pairing of the | chain with surrogate light chains and by association with the signaling molecules Iga and IgP. This receptor delivers survival and proliferation signals and also signals to inhibit rearrangement on the other heavy chain allele (allelic exclusion).
* As cells differentiate into immature B cells, V-J recombination occurs initially at the Ig k locus, and light chain proteins are expressed. Heavy and light chains are then assembled into intact IgM molecules and expressed on the cell surface. Immature B cells leave the bone marrow to populate peripheral lymphoid tissues, where they complete their maturation. At the mature B cell stage, synthesis of | and 8 heavy chains occurs in parallel mediated by alternative splicing of primary heavy chain RNA transcripts, and membrane IgM and IgD are expressed.
* During B lymphocyte maturation, immature B cells that express high-affinity antigen receptors specific for self antigens present in the bone marrow are induced to edit their receptor genes or these cells are eliminated. Receptor editing can involve further rearrangement at the Ig k locus and eventually also involve Ig X light chain gene rearrangement. B cells that express X light chains are frequently cells that have undergone receptor editing.
* T cell maturation in the thymus also progresses in stages distinguished by the pattern of expression of antigen receptor genes, CD4 and CD8 corecep-tor molecules, and location in the thymus. The earliest T lineage immigrants to the thymus do not express TCRs or CD4 or CD8 molecules. The developing T cells within the thymus, called thymo-cytes, initially populate the outer cortex, where they undergo proliferation, rearrangement of TCR genes, and surface expression of CD3, TCR, CD4, and CD8 molecules. As the cells mature, they migrate from the cortex to the medulla.
* The least mature thymocytes, called pro-T cells, are CD4-CD8- (double-negative), and the TCR genes are initially in the germline configuration at this stage. Rearrangement of the TCR p, 8, and y chain genes occurs at this stage.
* At the pre-T stage, thymocytes remain doublenegative, but V-D-J recombination is completed at the TCR p chain locus. Primary p chain transcripts are expressed and processed to bring a VDJ exon adjacent to a Cp segment, and TCR p chain polypeptides are produced. The TCR p chain associates with the invariant pre-Ta protein to form a pre-TCR. The pre-TCR transduces signals that inhibit rearrangement on the other p chain allele (allelic exclusion) and promotes differentiation to the stage of dual CD4 and CD8 expression and further proliferation of immature thymocytes. At the CD4+CD8+ (double-positive) stage of T cell development, V-J recombination occurs at the TCR a locus, a chain polypeptides are produced, and low levels of the TCR are expressed on the cell surface.
* Selection processes drive maturation of TCR-expressing, double-positive thymocytes and shape the T cell repertoire toward self MHC restriction and self-tolerance.
* Positive selection of CD4+CD8+ TCR ap thymo-cytes requires low-avidity recognition of peptide-MHC complexes on thymic epithelial cells, leading to a rescue of the cells from programmed death. As TCR ap thymocytes mature, they move into the medulla and become either CD4+CD8- or CD8+CD4-. Lineage commitment accompanies positive selection. It results in the matching of TCRs that recognize MHC class I with CD8 expression and the silencing of CD4; TCRs that recognize MHC class II molecules are matched with CD4 expression and the loss of CD8 expression.
* Negative selection of CD4+CD8+ TCR ap doublepositive thymocytes occurs when these cells recognize, with high avidity, antigens that are present in the thymus. This process is responsible for tolerance to many self-antigens. Medullary thymocytes continue to be negatively selected, and cells that are not clonally deleted acquire the ability to differentiate into either naive CD4+ or CD8+ T cells and finally emigrate to peripheral lymphoid tissues.
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