Development of Thymus from the Three Primary Germ Layers

1. Development of Thymus from the Three Primary Germ Layers Leukocytes from bone marrow colonize thymic anlage

3. T cells first produced in waves then reach a steady state

4. Precursor must choose

5. a:b T cells

6. preTCR of a:b T cells

7. Stages of a:b T Cell Maturation CD3

8. Specific Distribution of Cells

9. Most T cells die in the thymus by apoptosis Must productively rearrange TCR genes - otherwise they die a:b T cells must also survive selection

10. Selection is a two-step process Medulla

11. Impact of Positive Selection MHC Restriction

12. Positive Selection

13. Summary of Positive Selection • During DP stage, T cells interact with stromal cortical epithelial cells expressing both MHC class I & II • If T cells express TCR with affinity to self MHC + self peptide, T cells receive a positive signal They will proliferate, survive & go to the next stage • If T cells do not receive a positive signal, they die. Death by Neglect - a passive event • Surviving T cells are MHC restricted

14. Impact of Negative Selection Tolerance

15. Negative Selection

17. Summary of Negative Selection • Occurs after positive selection but before SP stage • T cells interact with dendritic cells & macrophages also expressing both MHC class I & II Bone marrow-derived stromal cells • Occurs deeper inside thymus near junction • If T cells express TCR with high affinity to self MHC + self peptide, they receive a negative signal & die Active event - kill T cells that could potentially cause autoimmune disease • Important mechanism for self tolerance • Surviving T cells become SP cells, enter medulla & leave the thymus as fully functional mature cells

18. Not positively selected Negatively selected Surviving cells

19. Requirements for T Cell Development cytokines All of these molecules are important Mutation in any one causes immunodeficiency disease

20. Defects Affecting a:b & g:d T Cells • TCR Defective RAG-1 or RAG-2 -> no T cells Causes Omenn's Syndrome Any defective TCR chain -> T cell problem • Signal transduction molecules Defective CD3 or Tyr kinases -> no T cells • Cytokines Common g chain of IL receptors -> no T cells Causes X-linked SCID Defective IL-7 -> no mature T cells

21. a:b T cells cytokines

22. Defects Affecting Only a:b T cells • MHC molecules Bare Lymphocyte Syndrome in humans results from various gene mutations Defective class I expression -> CD8+ T cell problem Defective class II expression -> CD4+ T cell problem Defective DM -> decreased CD4+ T cells but autoreactive mature T cells • CD4 & CD8 co-receptors Lack of respective T cell subpopulation

23. CD4 & CD8 cytokines

24. Choice between CD4 or CD8 Co-receptor • Decision of which co-receptor will be lost is final when positive selection is finished -> consensus • Differential activity of Tyr kinase p56 lck appears to be involved • Two models: Both supported by experimental results • #1 - Random loss of one co-receptor before positive selection occurs T cell survival depends on coordinated signals • #2 - Positive selection induces a signal to shut off expression of inappropriate co-receptor

25. starts