1. T-cell development central tolerance

2. The cellular organization of the thymus

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

4. DIFFERENTIATION AND MATURATION OF T CELLS IN THE THYMUS

5. Commitment to the T-cell lineage changes receptor expression Lack of IL7 signaling (IL7 or IL7R) stalls Early T-cell development SCIDs

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

7. 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

8. 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

9. 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.

10. 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

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

12. Nemazee Nature Reviews Immunology 6, 728–740 (October 2006) | doi:10.1038/nri1939

13. . T cell development and migration in the thymus.

15. Only a small fraction of T cells mature into functional T cells Positive selection: Occurs in the cortex, requires thymic epithelial cells (MHCI/MHCII positive) -Az αβ double-positive Thymocytes must recognize self-MHC. - First step, (Ca 2% of thymocytes survive!!) - Selection occurs in 3-4 days!! Positive selection --- results in clones that are reactive to self MHC. Basis of MHC restriction!!! Peptides are recognized in the context of self MHC

16. 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

17. Negative selection of T cells in the thymus. Elimination of potentially autoreactive clones. Requires several cell types besides epithelial cells: for example DC or macrophages In summary: development of central T cell tolerance is an integral part of T cell differentiation. T cells incapable of interacting with self-MHC/self-antigen complexes are eliminated during positive selection, whereas clones with intermediate or high affinity towards the same complexes will survive and become single-positive T cells. On the other hand, autoreactive clones with high affinity towards self- MHC/self-antigen complexes are eliminated during negative selection. An interesting cell type is the self-reactive regulatory T cells (Treg) that have high affinity TCRs, bordering at negative selection (B), and have important roles in maintaning peripheral tolerance (discussed later).

18. The response of the immune system to the stimuli of the outer and inner environment.

19. Immunological tolerance

20. Definition: Unresponsiveness to a given antigen induced by the interaction of that antigen with the lymphocytes; Antigen specific!!! Unlike immunosuppresion. 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, allrgic reaction or even tissue rejection.

21. Central T cell tolerance Central T cell is surprisingly effective mainly mediated by negative selection How can many tissue-restricted antigens (TRA) be expressed in medullary thymic epithelial cells (mTECs)?

22. Central and peripheral tolerance to self antigens. Elimination of self-reactive clones BUT!!! Some T-cell clones escape, Elimination of „fugitive” or altered clones important role for regulatory T- cells.

23. Autoimmun regulator (AIRE) AIRE is responsible for the expression of tissue antigens in the thymus Mutations in AIRE cause an autoimmune polyendocrine syndrome Lack of proper negative selection allows too many self reactive T-cell clones to leave the thymus Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)

24. Deficiency in establishing central T-cell tolerance: Autoimmune PolyEndocrinopathy- Candidiasis-Ectodermal Dystrophy (APECED), AIRE deficiency. AIRE: transcription factor inducing expression of many tissue-specific genes normally not expressed in the thymus. Rare disease, but more frequently seen in inbred populations Finnish, Iranian Jews and in the island of Sardine

25. Symptoms of APECED

26. apeced 85% hypoparathyreodism 75% adreal failure 60% ovarian failure 52% nail dystrophy 18% diabetes mellitus 100% mucocutaeous canndidiasis (MCM) Anti-Th17 specific antibodies !!!!! Role of Th17 discovered by studying a rare immunodeficiency https://jimneydandme.wordpress.com/james-story/