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DIFFERENTIATION AND MATURATION OF T CELLS IN THE THYMUS

DIFFERENTIATION AND MATURATION OF T CELLS IN THE THYMUS. The cellular organization of the thymus. The proportion of the thymus that produces T cells decreases with age. Commitment to the T-cell lineage changes receptor expression. Lack of IL7 signaling (IL7 or IL7R) stalls

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DIFFERENTIATION AND MATURATION OF T CELLS IN THE THYMUS

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  1. DIFFERENTIATION AND MATURATION OF T CELLS IN THE THYMUS

  2. The cellularorganization of thethymus

  3. The proportion of the thymus that produces T cells decreases with age.

  4. Commitment to theT-celllineagechanges receptor expression Lack of IL7 signaling (IL7 or IL7R) stalls EarlyT-celldevelopment SCIDs

  5. T-cell development is driven by the receptor Notch 1.

  6. a a REGULATED T-CELL DIFFERENTIATION APC CD4+CD8+ TCR preT- Epithelial cell immatureTcell pre Tcell ANTIGEN RECOGNIZING RECEPTOR pro T cell SIGNALING RECEPTOR NO ANTIGEN RECOGNIZING RECEPTOR

  7. α:β and γ:δ T cellsdevelopfrom a commondouble-negativeT-cellprogenitor. Only a few percent of the developing thymocytes lives, the rest areeliminated by apoptosis

  8. T-cell receptor gene rearrangements in double-negative thymocytes can lead to the expression of either a γ:δ receptor or a pre-T-cell receptor.

  9. Geneexpressionthroughthe stagesof α:β T-cell development in developing T cells.

  10. NemazeeNature Reviews Immunology6, 728–740 (October 2006) | doi:10.1038/nri1939

  11. POSITIVE SELECTION OF DOUBLE POSITIVE (DP) T CELLS ALSO DIRECTS CD4 AND CD8 SINGLE POSITIVE (SP) T CELL COMMITMENT POSITIVE SELECTION FOR 3 – 4 DAYS, SUCCESSIVE α-GENE REARRANGEMENTS BARE LYMPHOCYTE SYNDROME (BLS) Lack of MHC class I – no CD8+ cellsLack of MHC class II – no CD4+ cells

  12. SELECTION OF T LYMPHOCYTES IN THE THYMUS AICD – Activation Induced Apoptosis PERIPHERAL TOLERANCE UNDER THE CAPSULE • The primary T cell pool is biased to MHC-specificity (V genes) 1-2% for one allotype • Focusing the T cell pool to self MHC recognition (+) • Elimination of useless and self agressive clones (-) • CENTRAL TOLERANCE • Focusing the T cell repertoire for recognition of non self • CD4+ and CD8+ T cell use the same TCR repertoire • Individualized T cell repertoire available in the periphery • CD4 and CD8 co-stimulatory molecules are involved in positive selection IL-7-dependent proliferation CORTEX CD4-CD8- DN β+preTα TCRαβ CD4+CD8+ DP TCR(-) sMHC+sPsMHC+fPfMHC+fP selection CORTEX/ MEDULLA   NO  – selection MEDULLA – AICD αβTCR αβTCR CD4+CD8+

  13. SELECTION OF THE T CELL REPERTOIRE – CENTRAL TOLERANCE POSITIVE SELECTION – Thymiceducation (no instructionforspecificity) Lowavidityinteraction of MHC - selfpeptide - TCR Thymicepithelialcells Selfpeptidecomposition and concentration (foreignpeptidesarenotpresent) Lowpeptidedoseinducespositiveselection – specialligands 80-90% of DN (CD4-CD8-) T cells is NOT positivelyselected PASSIVE CELL DEATH BY NEGLECT NEGATIVE SELECTION – Centralselftolerance Highavidity of MHC - selfpeptide - TCR interaction Ubiquitous and abundantselfantigensarepresentinthethymus Highpeptidedoseinducesnegativeselection Anythymicantigenpresentingcell: epithelialcells, bonemarrow-derived macrophages, dendriticcells THE GENERATION OF SELF MHC + FOREIGN PEPTIDE SPECIFIC T CELLS REQUIRES WEAK INTERACTION WITH SELF MHC + SELF PEPTIDE SELF RESTRICTED AND TOLERANT PERIPHERAL T CELL REPERTOIRE PHYSIOLOGICAL TRESHOLD NOT COMPLETE

  14. γδT-cells • MHC-independent, CD1c and CD1d dependent • Doublemegative • comprise up to 50% of the intra-epithelial lymphocyte population • expandedinintracellularbacterialinfections(Mycobacteriumtuberculosis and Listeriamonocytogenes), extracellularinfections (Borreliaburgdorferi) • a population that is expanded in certain disease states such as celiac disease

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