DIFFERENTIATION AND MATURATION OF T CELLS IN THE THYMUS

The cellular organization of the thymus

A T-sejt fejlődésben fontos szerepet játszanak a Notch 1 receptorok

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

T- CELL DEVELOPMENT NK cell No rearrangement Lymphoid precursor Pro-T  -rearrangement T Pre-T  -rearrangement Pre-T  Selection clonal deletion T T T Mature-T Mature-B c-kit/CD44 H rearrangementSurrogate LL rearrangement Selection clonal deletion B B B B  Pro-B Pre-B RAG-1/RAG-2

1.Generation of NK cells – no TCR 2. Differentiation of γδ and αβ TCR carrying T cells 3. Selection of αβ TCR – positive selection – negative selection 4. Differentiation of CD4+ and CD8+ T cell lineages EVENTS OF T CELL DIFFERENTIATION IN THE THYMUS Early pre-T Pre-Tα-chain Lck signal β rearrangement γδ T-cell No selection γδ T-cell No selection αβCD4+ αβCD8+ CD4+CD8+ IL-7-dependent proliferation Pro-T unsuccesful β-chain unsuccesful α-chain no positive selection negative selection α rearrangement Late pre-T CD4+CD8+

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

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

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

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 NEGLECTION 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

Homozygote Heterozygote HOMEOSTASIS OF POSITIVE AND NEGATIVE SELECTION IN THE DEVELOPMENT OF THE AVAILABLE T LYMPHOCYTE REPERTOIRE Number of MHC molecules Ratio of positive selection Ratio of negative selection increases with the number of MHC genes

a a Activated T-cell Mature naive T-cell Memory T-cell T-CELL DIFFERENTIATION IN THE PERIPHERY Ag CD4 TCR APC CD8 TCR APC CD4 TCR APC CD8 TCR APC CD4 TCR APC CD8 TCR APC Ag