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 Early T-cell development SCIDs

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

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

α:β and γ:δ T cells develop from a common double-negative T-cell progenitor. Only a few percent of the developing thymocytes lives, the rest are eliminated by apoptosis

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.

Gene expression through the stages of α:β T-cell development in developing T cells.

Nemazee Nature Reviews Immunology 6, 728–740 (October 2006) | doi: /nri1939

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

1.The primary T cell pool is biased to MHC-specificity (V genes) 1-2% for one allotype 2.Focusing the T cell pool to self MHC recognition (+) 3.Elimination of useless and self agressive clones (-) 4.CENTRAL TOLERANCE 5.Focusing the T cell repertoire for recognition of non self same TCR repertoire 6.CD4+ and CD8+ T cell use the same TCR repertoire 7.Individualized T cell repertoire available in the periphery 8.CD4 and CD8 co-stimulatory molecules are involved in positive selection αβTCR CD4+ CD8+ SELECTION OF T LYMPHOCYTES IN THE THYMUS UNDER THE CAPSULE CORTEX CORTEX/ MEDULLA IL-7-dependent proliferation β+preTα CD4-CD8- DN CD4+CD8+ DP MEDULLA TCRαβ TCR(-) sMHC+sP sMHC+fP fMHC+fP  selection – selection  – AICD NO  PERIPHERAL TOLERANCE AICD – Activation Induced Apoptosis

POSITIVE SELECTION – Thymic education (no instruction for specificity) Low avidity interaction of MHC - self peptide - TCR Thymic epithelial cells Self peptide composition and concentration (foreign peptides are not present) Low peptide dose induces positive selection – special ligands 80-90% of DN (CD4-CD8-) T cells is NOT positively selected PASSIVE CELL DEATH BY NEGLECT NEGATIVE SELECTION – Central self tolerance High avidity of MHC - self peptide - TCR interaction Ubiquitous and abundant self antigens are present in the thymus High peptide dose induces negative selection Any thymic antigen presenting cell: epithelial cells, bone marrow-derived macrophages, dendritic cells 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 SELECTION OF THE T CELL REPERTOIRE – CENTRAL TOLERANCE

MHC-independent, CD1c and CD1d dependent Double megative comprise up to 50% of the intra-epithelial lymphocyte population expandedinintracellularbacterialinfections(Mycobacterium tuberculosis and Listeriamonocytogenes), extracellularinfections (Borreliaburgdorferi) a population that is expanded in certain disease states such as celiac disease γδ T-cells