T CELL BIOLOGY T cell development T cell activation T cell responses

1. Lecture Blocks • T CELL BIOLOGY • T cell development • T cell activation • T cell responses • SPECIAL CELLS, PLACES AND THINGS • NK Cells, Mucosa, Cytokines • IMMUNE REGULATION • Regulation of Immunity • Infections and vaccines • Autoimmunity/Tolerance • Immunology of Pregnancy

2. Course Material • Companion lecture notes in pdf on website • Responsible for material covered in class • Use textbook for enhanced understanding • Exam will be short and medium written answer

3. T Cell Development Lectures 2 & 3 • TCR structure • TCR Repertoire Formation • Development of  T cells • Repertoire Selection • MHC-restriction

4. T cells: Review T cells use their TCR to recognize antigens in a complex with MHC molecules MHC-II present extracellular antigens to CD4 T helper cells (TH) MHC-I present intracellular antigens to CD8 cytotoxic T cells (TC)

5. TCR = T cell receptor: Review Diverse Repertoire by Gene Rearrangement   Peptide From the Universe of Proteins + MHC = Gene Family with Extreme Polymorphism   For example Human MHC class I HLA-B >559 alleles

6. Each T cell has a unique TCR Antigen binding region TCR

7. T cell receptor structure

8. TCR MHC-I

9. TCR MHC-I

10. T cell co-receptors • CD8 on T cytotoxic cell binds to MHC I • CD4 on T helper cell binds to MHC II • Only have binding when TCR recognizes antigen + MHC

11. T cell co-receptors

12. T cell membrane Target cell

14. Germ-line organization - The other TCR The  locus is nested inside the  locus When α rearrangement is made, entire δ locus is deleted. T cells are αβ OR λδ NOT BOTH.

15. TCR Diversity – The germ line repertoire

16. TCR Diversity – The germ line repertoire Similar to antibody rearrangements: recombination involves heptamer/nonamer RSS, RAG and Ku • There are P and N nucleotide additions for all joins of TCR •  chain - VJ •  chain - VD and DJ joins

17. Complementarity-determining regions (CDRs)

18. TCR Diversity – Allelic Exclusion  Locus allelic exclusion Can produce  chains VJ Example VJ + VDJ VJ + VJ Unrearranged 

19. IG = 5x1013 compared to αβ TCR = 1018

20. Summary to this point Generation of TCR Diversity V(D)J recombination VDJ join = CDR3 CDRs interact with peptide-MHC Potential TCR repertoire = Tons TCR engagement with peptide–MHC Coreceptors CD4 and CD8

21. T Cell Development and Selection

22. Student Fate Decisions Hematopoietic Cell Fate Decisions T cell fate Biology PhD in Biology Mature T Cell Lymphocyte Progenitor Science NK cell fate Computing B cell fate Chemistry Environmental Activist Effector T cells HSC High School Completed Arts Myeloid Lineage D. Burshtyn

23. Cell Fate Decisions T cell fate Mature T Cell Lymphocyte Progenitor B cells NK cells HSC Effector T cells Myeloid Lineage D. Burshtyn

24. T Cell Education T cell precursors from the bone marrow enter the thymus and leave as mature T cells T T cell precursor Mature T cell Thymus T cells acquire their specificity, diversity, and ability to distinguish self from non-self in the thymus

25. T Cell Education An experiment to show TCR gene rearrangement and the thymus are required for generation of T cells T cells in spleen? No No

26. T cells in spleen? NO NO YES YES Conclusion: SCID thymus can correct the defect in nude mouse

27. Thymic Microenvironment Cortical epithelial cells

28. Thymic Cortex • Cortical thymic epithelial cells = stromal cells or “Nurse cells” • Provide growth factors (IL-7) • Contact dependent signals (c-kit, notch) cortex Thymic nurse cell Thymocyte • T cell precursors: • proliferate • begin to mature - ProT cell