Lymphocyte Development PDF

Sequential Events for Lymphocyte Development  The process by which lymphocyte progenitors in the thymus and bone marrow differentiate into mature lymphocytes that populate peripheral lymphoid tissues is called lymphocyte development or lymphocyte maturation  The greatest proliferative expansion...

Sequential Events for Lymphocyte Development  The process by which lymphocyte progenitors in the thymus and bone marrow differentiate into mature lymphocytes that populate peripheral lymphoid tissues is called lymphocyte development or lymphocyte maturation  The greatest proliferative expansion of lymphocyte precursors occurs after successfully rearranged the Ig heavy chain gene (B cell) or the TCR β chain gene (T cell). 2 Sequential Events for Lymphocyte Development  Commitment of progenitor cells to the B lymphoid or T lymphoid lineage.  Proliferation of progenitors and immature committed cells at specific early stages of development, providing a large pool of cells that can generate useful lymphocytes.  The sequential and ordered rearrangement of antigen receptor genes and the expression of antigen receptor proteins. (The terms rearrangement and recombination are used interchangeably.)  Selection events that preserve cells that have produced functional antigen receptor proteins and eliminate potentially dangerous cells that strongly recognize self antigens.  Differentiation of B and T cells into functionally and phenotypically distinct subpopulations. B cells develop into follicular, marginal zone, and B-1 cells; and T cells develop into CD4+ and CD8+ αβ T lymphocytes, natural killer T (NKT) cells, MAIT cells, and γδ T cells. 3 T Lymphocyte 4 Multipotent stem cells give rise to distinct B and T lineages The EBF, E2A, and Pax-5 transcription factors induce the expression of genes required for B cell development: Rag-1 and Rag-2 proteins Pre-B and the B cell receptor Down stream signaling proteins The Notch 1 and GATA3, signaling proteins induce the expression of genes required for T cell development: IgM Rag-1 and Rag-2 proteins IgD IL-7 is required for the proliferation of T cell progenitors: Mutations in the IL-7 gene rise to an immunodeficiency disorder in called X-linked severe combined immunodeficiency disease (X-SCID) 6  Epigenetic mechanisms that regulate Lymphocyte Development The methylation of DNA on certain cytosine residues that generally silences genes. Posttranslational modifications of the histone tails of nucleosomes (e.g., acetylation, methylation, and ubiquitination) that may render genes either active or inactive depending on the histone modified and the nature of the modification. Active remodeling of chromatin by protein machines called remodeling complexes that can also either enhance or suppress gene expression: * Commitment of developing T cells to the CD4 or CD8 lineage depends on epigenetic mechanisms that silence the expression of the CD4 gene in CD8+ T cells. The silencing of gene expression by noncoding RNAs: Deletion of Dicer, a key enzyme in miRNA generation, in the T lineage results in a preferential loss of regulatory T cells (Treg) and the consequent development of an autoimmune phenotype 7  Selection Processes That Shape the B and T Lymphocyte Repertoires The process of lymphocyte development contains numerous steps, called checkpoints. Pre-antigen receptors and antigen receptors deliver signals to developing lymphocytes that are required for the survival of these cells and for their proliferation and continued maturation. The pre-antigen receptor is the first checkpoint during lymphocyte development. In the next step of maturation, developing B and T cells express complete antigen receptors and the cells are selected for survival based on what these receptors recognize. Cells that express useful antigen receptors may be preserved, and potentially harmful cells that strongly recognize self structures may be eliminated. In the T cell lineage, positive selection ensures the maturation of T cells whose receptors recognize self major histocompatibility complex (MHC) molecules. The expression of the coreceptor on a T cell (CD8 or CD4) is matched to the recognition of the appropriate type of MHC molecule (class I MHC or class II MHC, respectively). Mature T cells whose precursors were positively selected by self MHC molecules in the thymus are able to recognize foreign peptide antigens displayed by the same self MHC molecules on antigen-presenting cells in peripheral tissues. 8  Checkpoints in Lymphocyte Maturation  Positive selection preserves receptor- expressing cells and is coupled to the generation of different B cell subsets  Negative selection is the process that eliminates developing lymphocytes whose antigen receptors bind strongly to self-antigens present in the generative lymphoid organs. 9 Stages of T Lymphocyte Maturation The αβ T cells mature into CD4+ class II MHC–restricted, or CD8+ class I MHC–restricted T cells 10 Domains of the TCR Protein variable constant domains domains CDRs : Complementary Determining regions 11 Germline Organization of Human TCR 12 Human TCR Repertoire 13 TCR Gene Recombination and Expression 14  T Lymphocyte Maturation in the Thymus  Thymic stromal cells, secrete IL-7, a critical lymphopoietic growth factor.  The movement of cells into and through the thymus is driven by chemokines. Cortex: CCR9:CCL25 Medulla: CCR7:CCL19/21 The cell death (Apoptosis) is due to a combination of factors, including: Failure to productively rearrange the TCR β chain gene and thus to fail the pre-TCR/β, Failure to be positively selected by self MHC molecules in the thymus, Self antigen–induced negative selection. 15 Pre-T Cell Receptor  the TCR β chain is expressed on the cell surface in association with an invariant protein called pre-Tα, along with CD3 and ζ proteins to form the pre-TCR complex.  TCR α gene expression in the double-positive stage leads to the formation of the complete αβ TCR.  Double-positive cells that successfully undergo selection processes go on to mature into CD4+ or CD8+ T cells 16  T Lymphocytes Subset in the Thymus  Functional and phenotypic differentiation into CD4+CD8− or CD8+CD4− single-positive (SP) T cells occurs in the medulla of the thymus, and mature T cells are released into the circulation.  Some double-positive cells differentiate into CD4+CD8− regulatory T cells (Treg CD4+)  The selection of developing T cells is dependent on recognition of antigen (peptide–MHC complexes) in the thymus and is responsible for preserving useful cells and eliminating potentially harmful ones.  Positive selection is the process in which thymocytes whose TCRs bind with low avidity (i.e., weakly) to self peptide–self MHC complexes are stimulated to survive and to differentiate either into CD4+ T cells or CD8+ T cells 18  Anti-CD4 mab Flow Cytometry Anti-CD8 19  Role of Co-stimulation in T Cell Activation The proliferation and differentiation of naive T cells require signals provided by molecules on APCs, called costimulators, in addition to antigen-induced signals 22 Costimulatory Pathways The interaction of CD40L on T cells with CD40 on APCs enhances T cell responses by activating the APCs. 23  Mechanisms of T cell costimulation by CD28. 24 Costimulation molecules of the CD28 family 25  Therapeutic Costimulatory Blockade CTLA-4-Ig is an approved therapy for rheumatoid arthritis and transplant rejection. Inhibitors of the CD40L:CD40 pathway are in clinical trials for transplant rejection and autoimmune diseases Antibodies that block the CTLA-4 and PD-1 inhibitory receptors are approved for the immunotherapy of tumors. They work by preventing CTLA-4 or PD-1 from binding their ligands, reducing inhibition and enhancing T cell activation and enabling the cancer-bearing individual to mount more effective antitumor immune responses. 26