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. 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!!

Classical MHC’s- there are others as well

2 MB!

4 MB!

2 copies of each!

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

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

Uptake of 3[H]thymidine

Th cells

These are seen as self

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

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!”

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

These are Chaperone proteins

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

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.