Chapter 7: The Development & Survival of Lymphocytes An. receptors carried by B & T lymphocytes variable in An. specificity?enabling immune response against wide range of pathogens Diverse repertoire of BCR & TCR generated during development of B cells & T cells from uncommitted precursors Production of new lymphocytes (lymphopoiesis) takes place in specialized lymphoid tissue (central lymphoid tissues) ( bone marrow for B cells, thymus for T cells Lymphocyte precursors originate in bone marrow An. specificity of individual lymphocyte determined early in differentiation?DNA sequences encoding variable regions of Ig in B cells & TCR in T cells assembled from gene segments Expression of An. receptor on surface of lymphocyte marks stage of development Next phase, receptor is tested for its An-recognition properties against molec. present in immed. environ. Specificity & affinity of receptor for ligands determines fate of immature lymphocyte Developing lymphocytes whose receptors interact weakly with self antigens receive survival signal ( positive selection Critical in development of T cells, which recognize An. as peptide bound to MHC molec. T cells that cannot recognize peptides bound to body?s own MHC molec. would not be able to amt an immune response against An. + selection ensures that individual will have repertoire of T cells that respond to peptides bound to self-MHC molec. In contrast, lymphocytes whose receptors bind strongly w/ self An. receive death signals ( negative selection Strongly self-reactive lymphocytes removed from repertoire before they become fully mature?initiate damaging autoimmune rxns Default fate of developing lymphocytes = death Final stages in development of mature lymphocyte?encounter with foreign An. activates to become effector or memory lymphocyte?discussed in later chapters Mature lymphocytes continually recirculate btwn blood & peripheral lymphoid tissue; numbers remain essentially constant Generation of lymphocytes in bone marrow & thymus In mammals, development of new T cells in thymus slows down B cells continually produced in bone marrow Successful gene rearrangement leads to production of protein chain that serves as signal for cell to progress to next development stage T cell development more complicated than B cell Accommodate production of two distinct lineages of T cells w/ diff TCR (?:? & ?:?) Further division of ?:? cells into CD4 & CD8 T cells?occurs in immature T cells after TCR genes assembled & expressed Lymphocyte development occurs in specialized environments & is regulated by signals from the environment along with the somatic rearrangement of An-receptor genes Lymphocytes develop from undifferentiated precursors/ stem cells that reside in bone marrow; descendants of pluripotent hematopoietic stem cells An. specificity of each lymphocyte determined through assembly of V, D, J gene segments to generate rearranged V gene exons encoding An-receptor variable (V) region Unsuccessful rearrangements do not result in protein ( nonproductive rearrangements Most of these loci can undergo successive rearrangements Nonproductive rearrange rescued by successful rearrange on other chromosome Successful (productive) rearrangement leads to synthesis of protein product, signal for cell to progress to next development stage To survive first stages of development B cells must make productive rearrange at Ig heavy chain locus & at one of the two light-chain locus T cells must make productive rearrange at either ?-chain locus & ?-chain locus to produce ?:? T cell, or at the ?-chain or ?-chain locus to produce ?:? T cells B cells develop in the bone marrow with the help of stromal cells & achieve maturity in peripheral lymphoid organs Contribution of stromal cells two-fold: Form specific adhestive contacts w/ developing B-lineage cells by interactions btwn cell-adhesion molec. & their ligands Provide soluble factors that control lymphocyte differentiation & proliferation Stages in B-cell development distinguished by expression of Ig chains & cell-surface proteins Earliest B-lineage cells: pro-B cells: early & late stage Productive VDJ rearrangement of heavy chain leads to expression Next main stage of development: pre-B cell: large & small All development up to this pt takes place in bone marrow; An. independent T cells also originate in the bone marrow, but all important events in development occur in thymus T cell precursors proliferate extensively in the thymus but most die there Developing T cells pass through a series of stages that can be distinguished by the expression of CD44 & CD25, the CD3:T-cell receptor complex proteins, & the co-receptors CD4 & CD8. The rearrangement of An-receptor gene segments controls lymphocyte development B cells undergo a programmed series of gene rearrangements in the bone marrow Two alleles for each Ig locus in diploid genome, each of which can rearrange, cell must prevent both alleles from make productive rearrangements or the cell will express 2 receptors of diff. An. specificity 3 successful joins required to express complete Ig molec. Successful rearrangement of H-chain Ig gene segments leads to formation of pre-B-cell that halts further V to DJ rearrangement & triggers cell to divide Interaction with self antigen selects some lymphocytes for survival but eliminates others Lymphocyte selection, how cells are screened for self destruction Immature B cells that bind self antigens undergo further receptor rearrangement, die, or are inactivated Apoptosis & elimination of immature self-reactive B cells predominates when interacting self An. is multivarient An. induced loss of cells from B cell population ( clonal deletion Mechanism for replacing receptors ( receptor editing Lymphocyte development involves both + and ? selection. - selection includes deletion from the repertoire, receptor editing, & anergy. For developing T cells, recognition of self-MHC:self-peptide complexes on thymic cortical epithelial cells provides positive survival signaling. Paradox: recognition can lead to 2 opposing effects (+ & - selection) Positive selection ensures functional matching of receptor, co-receptor, & the class of MHC molecule
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