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Transcript
DEVELOPMENT OF T LYMPHOCYTES ARPAD LANYI PhD [email protected] Further reading: Peter Parham, The Immune System 4th Ed. Chapter 5 (5.1-5.5), Chapter 7 THE CELLULAR ORGANIZATION OF THE THYMUS THE PROPORTION OF THE THYMUS THAT PRODUCES T-CELLS DECREASES WITH AGE Thymic involution occurs at a rate of 3%/year. Over 40 years of age bone marrow transplantation is unlikely to generate a full naive T-cell repertoire. EARLY PHASE Generation of antigen recognition receptors SELECTION Deletion Anergy BONE MARROW CD19 CD127 CD 34 CLP pro B pre B IgM pre pre pre preB B B Heavy chain Light chain B rearrangement pre pre pre rearrangement Imm B B B B Commitment CD2 CD127 THYMUS pro T CENTRAL TOLERANCE Allelic exclusion Receptor editing 1st checkpoint 2nd checkpoint β-chain rearrangement γ-, δ-chain rearrangement γδ T Negative selection α-chain rearrangement pre pre T pre T γ-, δ-chain pre pre T rearrangement pre T T pre pre T γδ T T T DP T Negative selection Positive selection SECONDARY LYMPHOID TISSUES IgM;IgD Tr. B IgM;IgD Positive selection Treg CD4 CD8 MHC restriction Death by neglect Deletion Mat B COMMITMENT TO THE T-CELL LINEAGE IS DRIVEN BY THE NOTCH 1 RECEPTOR COMMITMENT TO THE T-CELL LINEAGE CHANGES RECEPTOR EXPRESSION Lack of IL7 signaling (IL7 or IL7R) stalls early T-cell development. SCIDs. Cells are beginning to rearrange the TCR loci TCR β-, α-, δ- and γ-chain loci The basic rules of TCR rearrangement are identical to that of the BCR Each germline TCR locus includes variable (V), joining (J) and constant (C) gene segments TCR β and TCR δ loci have D segments, like the Ig heavy chain locus δ gene segments are embedded within the a-chain locus α-chain gene rearrangement results in the deletion of the δchain locus REARRANGEMENT OF β, γ AND δ LOCI STARTS AT THE SAME TIME If δ- and γ-chain genes rearrange before βchain, γ:δ receptor assembles variable region (V) constant region (C) transmembrane region cytoplasmic tail γδ T-cells •MHC-independent, CD1c and CD1d dependent. •Double megative. •Comprise about 1-5% of the T-cells found in the circulation, but can be the dominant (up to 50%) T-cell population in epithelial tissue. •A population that is expanded in intra(Mycobacterium tuberculosis and Listeria monocytogenes) and extracellular pathogens (Borrelia burgdorferi) and certain disease states such as celiac disease. REARRANGEMENT OF β, γ AND δ LOCI STARTS AT THE SAME TIME If β-chain gene rearranges before δ- and γ-chain genes, pre T-cell receptor assembles (the more frequent outcome of the competition) 1ST CHECKPOINT β-chain is tested for its capacity to bind to an invariant polypeptide called pTα, which acts as a surrogate α-chain A nonproductively rearranged β-chain gene can be rescued by a second rearrangement at the same locus This possibility is not available to the immunoglobulin heavychain genes, because the V-DJ recombination excises all the non-rearranged D segments. If a rearrangement at one β-chain locus is nonproductive, a thymocyte can attempt a rearrangement at the β-chain locus on the homologous chromosome Thymocytes can make FOUR attempts to rearrange the βchain gene 80% of thymocytes make a productive rearrangement of the β-chain gene, compared with a 55% success rate for heavychain gene rearrangement by developing B cells. SUCCESSIVE GENE REARRANGEMENTS ON TCRα LOCI Multiplicity of V (~70) and J gene ( 61) segments allows many attempts 2ND CHECKPOINT α-chain is tested for its capacity to bind the β-chain and assembles a T-cell receptor SUMMARY FOR EARLY STAGES OF T-CELL DEVELOPMENT Cells are now ready for positive and negative selection Only a small fraction of T cells mature into functional T cells POSITIVE SELECTION -Occurs in the cortex, requires thymic epithelial cells -αβ double-positive thymocytes must recognize selfMHC/auto-antigen complex -Continuing α-chain gene rearrangement increases the chance for positive selection -Ca. 10-12% of thymocytes survive! Positive selection --- results in clones that are reactive to SELF MHC. BASIS OF MHC RESTRICTION!!! Positive selection of double positive (dp) T-cells also directs CD4 and CD8 single positive (sp) T-cell commitment THYMIC EPITHELIAL CELLS ARE MHCI/MHCII POSITIVE! BARE LYMPHOCYTE SYNDROME (BLS) Lack of MHC class I – no CD8+ T-cells Lack of MHC class II – no CD4+ T-cells The response of the immune system to the stimuli of the outer and inner environment Environment Immune system Tolerance Self Non-self Dangerous Pathogenic Immune response Immunological tolerance Definition: Lack of adaptive immune response against a given antigen. The interaction of the antigen with the lymphocytes induces unresponsiveness. ANTIGEN SPECIFIC!!! Unlike immunosuppression. Why is this important? -All individuals are tolerant to their own antigens (self tolerance). -Failure of self tolerance results in autoimmunity. -Terapeutic potential: Treat autoimmune diseases, allergic reaction or even tissue rejection. T-cells with high affinity TCR towards the self MHC/self peptide complex are eliminated, but clones with intermediate affinity survive. NEGATIVE SELECTION Elimination of potentially CENTRAL TOLERANCE KEYWORD: AFFINITY of T-cells in THE the thymus autoreactive clones A percentage of self-reactive T-cells – that have high affinity TCRs, bordering negative selection – will survive the negative selection process and differentiate into regulatory T-cells. CENTRAL T-CELL TOLERANCE MEDIATED BY NEGATIVE SELECTION IS SURPRISINGLY EFFECTIVE. HOW CAN TISSUE-RESTRICTED ANTIGENS BE EXPRESSED IN MEDULLARY THYMIC EPITHELIAL CELLS? AUTOIMMUN REGULATOR (AIRE) A transcription factor expressed by thymic medullary epithelial cells and induces expression of many tissue-specific genes Deficiency in establishing central T-cell tolerance allows too many self reactive T-cell clones to leave the thymus AUTOIMMUNE POLYENDOCRINOPATHYCANDIDIASIS-ECTODERMAL DYSTROPHY (APECED) Rare disease, but more frequently seen in inbred populations Finnish, Iranian Jews and in the island of Sardine SYMPTOMS OF APECED • Anti-Th17 specific antibodies!!!!! • Role of Th17 discovered by studying a rare immunodeficiency • https:///jimneydandme.wordp ress.com/james-story SUMMARY EARLY PHASE Generation of antigen recognition receptors SELECTION Deletion Anergy BONE MARROW CD19 CD127 CD 34 CLP pro B pre B IgM pre pre pre preB B B Heavy chain Light chain B rearrangement pre pre pre rearrangement Imm B B B B Commitment CD2 CD127 THYMUS pro T CENTRAL TOLERANCE Allelic exclusion Receptor editing 1st checkpoint 2nd checkpoint β-chain rearrangement γ-, δ-chain rearrangement γδ T Negative selection α-chain rearrangement pre pre T pre T γ-, δ-chain pre pre T rearrangement pre T T pre pre T γδ T T T DP T Negative selection Positive selection SECONDARY LYMPHOID TISSUES IgM;IgD Tr. B IgM;IgD Positive selection Treg CD4 CD8 MHC restriction Death by neglect Deletion Mat B THANK YOU NEGATIVE SELECTION of T-cells in the thymus CENTRAL TOLERANCE Elimination of potentially autoreactive clones T-cells with high affinity TCR towards the self MHC/self peptide complex are eliminated, but clones with intermediate affinity survive. A percentage of self-reactive T-cells – that have high affinity TCRs, bordering at negative selection – will survive the negative selection process and differentiate into regulatory T-cells. THE KEYWORD: AFFINITY