Introduction to Immunology

1. Introduction to Immunology Jianzhu Chen Department of Biology Massachusetts Institute of Technology jchen@mit.edu • Principles of adaptive immunity • TCR recognition • Antigen presentation and processing • Host defense against viruses

2. Innate Adaptive Cells Ag receptors Ag recognition Speed Memory Innate immunity: Preformed, non-specific effectors. Adaptive immunity:Immune mechanisms that are mediated by T and B lymphocytes and that change in response to infection.

3. Principle of the Adaptive Immunity What is fundamental challenge faced by the immune system? Fact: Strategy: Solution:

4. What are the consequences of using V(D)J recombination to create antigen receptor diversity?

5. V V V V a V Key molecules and cells of the adaptive immunity 3 molecules 3 cell types 4 cardinal features Antigen-presenting cells (APC) Dendritic cells (DC) Macrophage B cells B cells T cells

6. Antigen recognition by BCR and TCR

7. TCR-peptide-MHC (pMHC) interaction

8. MHC Structure Wiley et al. 1987 peptide

9. TCR-pMHC interaction Extensive contacts: between TCR and peptide between TCR and MHC TCR molecules are evolved to bind to MHC

10. TCR-pMHC interaction

11. Major Histocompatibility Complex (MHC) 1930s: Peter Gorer identified four groups (I, II, III, and IV) of blood cell antigens in inbred mice. 1950s: George Snell established the group II antigens mediate rejection of transplanted tumors and other tissues. Histocompatibility antigens (H-2 in mouse) Human Leukocyte Antigens (HLA in human)

12. MHC Restriction MHC type determine the ability of T cell response. Zinkernagel & Doherty, 1975

13. a MHC Structure Similar to Ig and TCR, belongs to the Ig superfamily

14. Two compartments of the cell

15. MHC Structure Class I  + 2m (2 microglobulin) Class II  +  subunits peptide peptide 2 1 1 1 Model: 3 2m 2 2 Simplified: Gene: a3 Tm L a1 a2 C C Peptide-binding proteins Peptide is part of the stable structure (heterotrimers)

16. MHC Structure Class I Class II Peptide binding cleft Peptide binding cleft b2m

17. MHC Structure

18. MHC Structure

19. MHC Structure Cell MHC Denature Peptide mass spectrometry Peptide Sequence

20. MHC Structure

21. TCR-pMHC interaction

22. MHC Structure

23. MHC Structure

24. MHC Structure

25. MHC Nomenclature Mouse H2-K -D -L H2-IA -IE Class I Class II HLA-A -B -C HLA-DP -DQ -DR • Human • Human • Leukocyte • Antigen Example: HLA-A2 (or A2), human MHC class I A molecule, allele 2 Haplotype: each set of alleles • H2-Kd (Kd)IAd • Balb/c  H-2dH2-Dd (Dd)IEd • H2-Ld (Ld)

26. MHC Function DP DQ DR HLA-C HLA-B HLA-A 2b 2a 3b 2a 3b 1a How can a small number of MHC molecules present a large number of peptides for TCR recognition? • Polygenic Possible MHC class I combinations in one individual: 2A + 2B + 2C = 6

27. MHC Function DP DQ DR HLA-C HLA-B HLA-A 2b 2a 3b 2a 3b 1a 89 19 45 20 350 2 470 110 240 How can a small number of MHC molecules present a large number of peptides for TCR recognition? • Polygenic • Polymorphic Presence of multiple alleles at a given locus within a species Possible MHC class I combinations in the human population: 470 x 110 x 240 = 1,240,800

28. MHC Function Differences in amino acids are concentrated in the peptide-binding groove. Different MHC molecules bind to different set of peptides How can a small number of MHC molecules present a large number of peptides for TCR recognition? • Polygenic • Polymorphic • Extremely polymorphic • 5%  20 a.a.

29. MHC Function DP DQ DR HLA-C HLA-B HLA-A 2b 2a 3b 2a 3b 1a 89 19 45 20 350 2 470 110 240 How can a small number of MHC molecules present a large number of peptides for TCR recognition? • Polygenic • Polymorphic • Co-expression • Presentation of multiple peptides per MHC molecule >2,000 peptides per class I molecule >> 2,000 peptides per class II molecule ~105 molecules per cell