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

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.

More details in to come!

More details in to come!

“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.

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.

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!

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

OK- back to MHCs- structure of MHC I

MHC I structure

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

MHCII- not only a dimer, but a dimer of dimers Open cleft- hold 13-18 AA peptides http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?uid=7120

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.

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

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 !

Linkage disequilibrium The diversity isn’t as great as theoretically expected Some alleles are found together more than you would expect: HLA-A1- 0.16; HLA B8- 0.09; Expecte 0.16X 0.09= 0.014; actual is 0.088- they are found together >6X as often as expected.

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

Many are autoimmune

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

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.

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

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

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

Antigen Processing and Presentation

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

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

“The TUNNEL OF DEATH!”

TAP= transporter for antigen processing

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

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

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

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

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.