1. Antigen presentation to T lymphocytes Chapter 5

2. Objectives Explain and illustrate the mechanisms of antigen processing for presentation on –MHC I –MHC II Describe how polygeny and polymorphism contribute to variation in MHC in a population

3. Antigen processing Antigen processing: degradation of proteins into peptides that can be presented on MHC I or MHC II –MHC I presents peptides derived from cytoplasmic antigens –MHC II presents peptides derived from extracellular or intravesicular antigens

4. Antigens are derived from cytosolic or vesicular compartments

5. Antigen processing for MHC I Cytoplasmic proteins are degraded by the proteasome

6. Antigen processing for MHC I The proteasome exists in two forms: –Constitutive –Immunoproteasome (interferon-inducible)

7. Antigen processing for MHC I MHC I is a transmembrane protein made in the ER Cytoplasm-derived peptides must be transported into the ER to bind MHC I

8. Antigen processing for MHC I

9. MHC I antigen processing animation

10. Antigens are derived from cytosolic or vesicular compartments

11. Antigen processing for MHC II Extracellular proteins are processed in endosomes by hydrolytic enzymes

12. MHC II expression pattern in cells Wubboltz et al, J Cell Biol 135:611-622, 1996 Lysosome marker GFP-tagged MHCII Both signals

13. Antigen processing for MHC II The invariant chain (Ii) blocks the MHC II peptide-binding cleft while it is in the ER Acid proteases cleave Ii but leave a fragment (CLIP) in the peptide- binding groove

14. Antigen processing for MHC II

15. MHC II antigen processing animation

16. GFP-tagged Mycobacterium tuberculosis Acidotropic dye (fluoresces in acidic vesicles) Guitierrez et al, Cell 119:753-796, 2004 Rap = rapamycin (antibiotic)

17. Humans have many variants of MHC I and II Human MHC proteins are called Human Leukocyte Antigen (HLA) class I and class II HLA molecules are polygenic and highly polymorphic Each HLA I or HLA II has a different range of peptide binding specificities

18. Organization of HLA genes

19. Polymorphism of HLA genes # of alleles (as of 1/04)

20. Polygeny and polymorphism of HLA