1. Chapter 8- MHC’s & Antigen Presentation
Where we’re going in this
MHC I and II functions review
Genes for these proteins
Structure in detail, and how that relates to Ag presentation
MHC’s and disease
Antigen presentation- some details, plus learning about processing in the Golgi

2. We need to be able to present lots of different peptides
We need to be able to present lots of different peptides. For this we need a somewhat generic binding, and much diversity.

3. More details in to come!

4. More details in to come!

5. “the nomenclature is somewhat confusing” HA!! MASSIVE UNDERSTATEMENT!!
2 MB!
2 copies of each!
4 MB!
Classical MHC’s- there are others as well
What we need to know: three, not 2 classes; functions of the three classes; and the existence of other, non-classical MHC’s.

6. A digression into mouse genetics
The MHC genes typically are a package deal- Haplotypes
We have inbred strains of mice- these are homozygous at the MHC’s, and have sets of MHC’s.

12. Mouse MHC terms Syngeneic- identical- a mouse strain
Congenic- the same except at one location- for our purposes, the same MHC haplotype-
E.g., B10.A: a B10 mouse with a type A haplotype
These terms will come into play later!

13. Strains are produce by breeding; useful in determining the effects of MHC’s on immune response

14. OK- back to MHCs- structure of MHC I

16. MHC I structure

17. Ends are closed; holds peptide of 8-10 AA’s

18. MHCII- not only a dimer, but a dimer of dimers
Open cleft- hold AA peptides

23. Different MHCI’s
Very interesting study. It shows that 1) different MHC I’s bind different peptides and 2) the peptides bound by a particular MHCI will have certain characteristics.

24. With MHC I, the peptide can bulge; not so with MHCII

26. Diversity! Multiple genes, now MANY alleles!
MHC genes are polymorphic:
Human MHC I- HLA A: 370
HLA B: 660
HLA C: 190
Lots of diversity in MHC II as well- DP, DQ, DR genes, and among the alpha and beta subunits.
Total theoretical diversity of 4 X 1019 !

27. Linkage disequilibrium
The diversity isn’t as great as theoretically expected
Some alleles are found together more than you would expect:
HLA-A ; HLA B ;
Expecte 0.16X 0.09= 0.014; actual is they are found together >6X as often as expected.

28. Diversity- so what? Differences in immune responsiveness
Some MHC’s linked to disease susceptibility

30. Many are autoimmune

31. So a completely heterozygous mouse would have 8 different MHC II molecules and six different MHC I molecules on its cell surfaces.

33. What to know I won’t test on this, but it’ll be helpful to know
- H2 D,L,&K are MHC I’s in mice
HLA A,B,C are MHC I’s in people
Three MCH I genes in mice and people
Three MCH II genes in people, 2 in mice.
They are polygenic and polymorphic
Structure of I and II’s- effect on size and types of peptides bound.
Effects on immune response and disease susceptibility, and why that might be.

34. MHC Restriction Tough concept
Fundamentally, T cells only recognize Ag presented by the MHC’s that they were trained to recognize in the thymus.

35. These do exogenous Ag presentation
Th cells
Uptake of 3[H]thymidine

36. For this experiment, the Ag that’s presented is not seen- wrong MHC!
These are seen as self

37. Antigen Processing and Presentation

38. Processing: Breaking up the antigen into pieces that fit into the MHC I or II groove.
Presentation: putting the peptides on the groove.
Again, endogenous and exogenous antigens

39. These are MHC II APC’s Non-pro’s get activated by inflammation!

41. “The TUNNEL OF DEATH!”

42. TAP= transporter for antigen processing

43. LMP’s- induced by infection, make production of MHC I peptides more likely

45. ERp57- ER protease, mw 57K- exoprotease, trims down to ~8 AA’s!
These are Chaperone proteins

46. Now- onto exogenous- receptor- mediated endocytosis, OR phagocytosis

48. HLA-DM- non-classical MHC- catalyst for exchange of CLIP for peptide

49. What to know
Definitions- processing, presentation, MHC restriction- evidence for the latter.
Tell the story of antigen presentation, beginning with the antigen until it’s on the surface of the cell-
MHCI- roles of ubiquitin, LMP’s, proteasome, TAP, tapasin, calreticulin, calnexin (chaperones)
MHC II- roles of invariant chain, CLIP, MHC DM, endocytic processing.