1. GENERATION OF LIGANDS FOR THE TCR
March 24, 2009
10:00-11:00

2. MHC MOLECULES BIND PEPTIDES
MHC molecules can bind many different peptides
MHC class I and class II bind different types of peptide
The shape of the peptide binding groove determines the
type of peptide that can be bound

3. THE MHC CLASS I BINDING SITE IS A CLOSED GROOVE
Closed groove = peptides are restricted in size

4. PEPTIDES BIND MHC CLASS I BY THEIR ENDS
Peptides that bind Class I are 8-10 amino acids long

5. MHC CLASS II BINDING GROOVE IS OPEN
Open groove = binding of peptides of variable length

6. PEPTIDES MAKE MULTIPLE CONTACTS WITH MHC CLASS II
MHC class II can accommodate peptides between amino acids long

7. AT THE DIAMOND:
MHC Class I = Big bun, little hot dog
MHC Class II = Little bun, big hot dog

8. THE SOURCE OF THE PEPTIDE DETERMINES IF IT
ASSOCIATES WITH MHC CLASS I OR CLASS II

9. PATHOGENS END UP IN DIFFERENT CELLULAR COMPARTMENTS
A cell can be divided into 2 compartments:
cytosol
vesicular system
Pathogens that live inside a cell, e.g., viruses
and bacteria that replicate intracellularly,
are in the cytosol
Some pathogens (bacteria) or their toxins
get taken up by cells and are found in
vessicles.

10. Processing and Presentation of Cytosolic Proteins

11. MHC CLASS I MOLECULE
Note: MHC Class I is a single chain associated on membrane
with b2 microglobulin

12. ASSOCIATION OF PEPTIDES WITH CLASS I: GENERATION OF PEPTIDES
The cytosol contains a large, multi-
subunit protein complex called the
PROTEASOME
The proteasome degrades proteins
into 8-10 amino acid peptides
TAP, a.k.a, transporter associated
with antigen processing, carries
peptides into the ER

13. Figure 3-18 part 1 of 2 ASSOCIATION OF PEPTIDE WITH MHC CLASS I
Association of MHC Class I with TAP
Figure 3-18 part 1 of 2
Chaperones (calnexin or calreticulin)
stabilize MHC class I
Peptide ready complex: MHC class I,
b2 microglobulin, tapasin, TAP

14. Figure 3-18 part 2 of 2 ASSOCIATION OF PEPTIDE WITH MHC CLASS I
MHC Binds Peptide and Is Expressed
Figure 3-18 part 2 of 2
MHC Class I must associate
with a peptide to be expressed
Most MHC Class I molecules
contain self peptides

15. Processing and Presentation of Extracellular Proteins

16. MHC CLASS II MHC class II is an ab heterodimer
Each chain has a peptide binding site associated with an Ig-like domain

17. ASSOCIATION OF PEPTIDES WITH CLASS II: GENERATION OF PEPTIDES
Extracellular antigen is taken up by vesicles called endosomes
The pH of the endosome drops
Reduced pH activates proteinases that generate peptides

18. MHC CLASS II a AND b CHAINS DIMERIZE IN THE ER
In the ER, MHC Class II molecules are associated with Ii
Ii sits in the peptide binding groove
MHC Class II + Ii leave the ER in a vesicle
In the vesicle, Ii is cleaved. But the CLIP fragment remains in the groove

19. MHC CLASS II ASSOCIATES WITH PEPTIDE
The vesicle containing MHC Class II fuses with the endosome
Peptide can’t bind…CLIP is in the groove
HLA-DM causes the release of CLIP
Peptide gets in the groove and the complex gets expressed

20. CO-RECEPTOR ASSOCIATION WITH MHC
MHC class I binds CD8
MHC class II binds CD4

21. TCR RECOGNIZES BOTH PEPTIDE AND MHC
Both chains of the TCR contact both peptide and MHC
TCR only binds peptide presented by the correct (self) MHC

22. MHC PATTERNS OF EXPRESSION REFLECT FUNCTION
CD8 cells:
Kill
Recognize Class I
Cells that might need to be killed
express Class I
CD4 cells:
Help
Recognize Class II
Cells that can activate CD4s
express Class II
MHC Class I is on all nucleated cells
MHC Class II is only on “professional” APC

23. A STRATEGY TO EFFECTIVELY FIGHT PATHOGENS
Peptides associate with the class of MHC that will stimulate the
subset of T cells that is best fitted to eliminate the pathogen

24. A WELL CO-ORDINATED ATTACK
The promoters of genes involved in antigen processing and
presentation are activated by a common factor (CIITA)
During an inflammatory response interferon g is secreted
Interferon g induces expression of CIITA

25. SUPERANTIGENS BYPASS THE NORMAL RECOGNITION MECHANISM
Staphylococcal enteroxin
Toxic shock syndrome toxin-1
Activate large numbers of
T cells in an antigen non-specific
leads to excess production
of mediators
Bridge MHC and TCR