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Download Features of B lymphocyte development
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Lymphocyte Development & Generation of Lymphocyte Antigen Receptors • Pin Ling (凌 斌), Ph.D. ext 5632; [email protected] • References: 1. Abbas, A, K. et.al, Cellular and Molecular Immunology (6th ed., 2007), Chapter 8 Questions What is the Bare Lymphocyte Syndrome? An immunodeficiency disease Lacking Class-II MHC expression Mutations in transcriptional factors regulating Class II expression, ex. CIITA What is the advantage of MHC Polymorphism? Is that good if MHC is as diverse as Ig or TCR? MHC polymorphism may provide a broader protective immunity in a population during pathogen infection . Outline • Overview of Lymphocyte Development • Generation of Diversity in Lymphocyte Ag receptors • B & T Lymphocyte Development • Summary & Question Key Concepts in lymphocyte development 1. Lymphocyte development-A process of differentiation of lymphoid progenitor cells into mature lymphocytes (T & B). 2. Rearrangement and expression of Ag receptor genes are associated with lymphocyte development. 3. Selection events are involved in preserving cells w/ correct Ag receptors and eliminating dangerous cells w/ self-recognition Ag receptor 4. Proliferation in the early lymphocyte development is stimulated by IL-7. Stages of lymphocyte development-I Checkpoints in lymphocyte development Selections in lymphocyte development Pluripotent HSCs => lymphocyte lineages Outline • Overview of Lymphocyte Development • Generation of Diversity in Lymphocyte Ag receptors • B & T Lymphocyte Development • Summary & Question Key Concepts in Diversity of lymphocyte Ag receptors 1. The germline organizations of Ig & TCR are similar. a. Multiple (V)ariable, (D)iversity, & (J)oining gene segments. b. These gene segments are spatially separated on the chromosomes 2. During lymphocyte development, gene rearrangement of Ag receptor genes occurs: a. Combinatorial diversity - Non-homologous DNA recombination (VDJ recombination) - Lymphoid-specific enzymes- RAG1 & RAG2 Other factors-DNA-PK, TdT, Ku, DNA ligase IV… b. Junctional diversity - Addition or removal of nucleotides among V (D)J joints -The largest contribution to diversity of Ag receptors In 1970s, Scientists thought 105 genes in human body => Antibodies over 1010 ? => Limited gene segments Hybrid-DNA nature (Recombination) Diverse Ab products Germline organization of Human Ig loci D segment in H chain Germline organization of Human TCR loci D segment in b chain Domains of Ig & TCR proteins HV3 or CDR3 Generation of Diversity in Ag receptor genes V(D)J Recombination-I 1. Recombination Signal Sequence (RSS): Heptamer & Nonamer => separated by 12or 23- spacers => Recognized by Recombinase 2. Deletion-VJ exons have the same orientation 3. Inversion – VJ have the different orientation V(D)J Recombination-II V(D)J Recombination III – Junctional Diversity Junctional diversity=> the greatest variability at HV3 (CDR3) Generation of Diversity in Ig or TCR Generation of Diversity in Ig or TCR Overview of Ig gene rearrangement Outline • Overview of Lymphocyte Development • Generation of Diversity in Lymphocyte Ag receptors • B & T Lymphocyte Development • Summary & Question Pluripotent HSCs => lymphocyte lineages II 1. Regulated by transcriptional factors 2. Notch-1 & GATA3 => T EBF, E2A & Pax-5 => B Features of B lymphocyte development 1. Maturation of B Lymphocytes development - Rearrangement & expression of Ig gene in a precise order - Selection & proliferation of pre-B cells via pre-Ag receptor 2. Selection of the mature B cell repertoire - Self Ag => Affect the strength of the BCR signal - Immature B cells => self Ag/high avidity => Receptor editing => Additional L chain recombination => Not Self-reactive => Fail to receptor editing => Apoptosis 3. During this maturation, B cell lineage cells go through distinct stages => A specific Ig gene expression => Distinct surface markers 4. At Pre-B cell stage, H chain recombination occurs first and associates w/ Surrogate light chains (l5 & VpreB). - l5 & VpreB are similar to k & l light chains but invariant - form pre-B cell receptor => Development Stages of B lymphocyte development-I Stages of B lymphocyte development-II Pre-B cell & Pre-T cell receptors Stages of B lymphocyte development-III Receptor Editing–2nd Chance Features of T lymphocyte development 1. Maturation of T Lymphocytes development - Sequential Rearrangement & expression of TCR genes - Selection & proliferation of T cell repertoire 2. Selection of the mature T cell repertoire occurs in Thymus - Positive selection => Self MHC-restricted - Negative Selection => Self Ag-MHC/high avidity => Apoptosis => Central Tolerance 3. CD4 & CD8 are surface markers for differentiation of Thymocytes (immature T cells). Stages of T lymphocyte development-I Maturation of T lymphocytes in Thymus CD4 & CD8 expression on Thymocytes Selection of T lymphocytes in Thymus TCR transgenic mouse model => T cell selection Outline • Overview of Lymphocyte Development • Generation of Diversity in Lymphocyte Ag receptors • B & T Lymphocyte Development • Summary & Question SUMMARY 1. Rearrangement and expression of Ag receptor genes regulate B & T lymphocyte development. 2. Selection events are involved in preserving cells w/ correct Ag receptors and eliminating dangerous cells w/ self-recognition Ag receptor 3. Gene rearrangement of Ag receptor genes occurs during lymphocyte development. - The basic mechanism is common to both B & T cells - Generate the Combinatorial diversity by randomly combining different V(D)J gene segments - Generate the Junctional diversity by filling the gap betweenjointed gene segments Question What is happened to the immune system if RAG1 & RAG2 are mutated?