Antigen Recognition and MHC

Question 1

What are the major classes of T cells?

Answer 1

1. CTLs (cytotoxic T cells) - induce cell death
2. Th (T helper cells) - secrete cytokines to modulate immune response of innate and adaptive IS (most B cells rely on Th signals and cytokines)

Question 2

What allows Ag recognition on CTLs and Th?

Answer 2

CTLs express CD8 co-receptor

Th express CD4 co-receptor and requires presentation by MHC molecules on APCs or target cells

Question 3

Compare MHC Class I and Class II

Answer 3

Class I:
Single polypeptide (alpha)
3 structural domains: alpha1, alpha2, alpha3
peptide binding groove b/w alpha1 and alpha2
Beta-2 microglobulin attached as stabilizing protein
expressed on most nucleated cells
Ag is presented to CD8 T cells (CTLs)
Presents endogenous Ags
HLA-A, B &C
8-10 amino acids
Class II:
heterodimer w/ beta and alpha chains
2 structural domains in each chain: alpha1, alpha2, beta1, beta2
Expressed on APCs, Ag presentation to CD4 T cells
Exogenous Ags expressed
HLA-DR, -DP, and DQ
13-25 amino acids

Question 4

What is promiscuous binding specificity?

Answer 4

Each MHC can potentially bind to many different polypeptide sequences (Ags), which is opposite of the specificity seen with TCRs and Abs

Question 5

What does a TCR recognize on other cells?

Answer 5

Both the peptide antigen and the MHC

Question 6

Where do the CD8 and CD4 co-receptors bind on the MHC?

Answer 6

CD8 binds to the alpha3 domain of MHC class I
CD4 binds to the beta2 domain of MHC class II

Question 7

Where are MHC class I and class II expressed?

Answer 7

MHC class I are expressed on most nucleated cells (low in CNS) indicating that most have the potential for destruction
MHC class II are expressed only on professional APCs: macrophages, dendritic cells and B cells

Question 8

What are the MHC class I isotypes?

Answer 8

HLA-A, HLA-B and HLA-C

These are co-dominantly expressed

Question 9

What are the MHC class II isotypes?

Answer 9

HLA-DR, HLA-DQ and HLA-DP

These are co-dominantly expressed and only on professional APCs

Question 10

How many isotypes are expressed on APCs?

Answer 10

All 6 isotypes of HLA surface proteins: HLA-A, -B, -C, DP, DQ, and -DR

Question 11

Explain HLA polymorphism

Answer 11

There is great genetic variability in MHC genes between individuals. This variability is concentrated in the peptide binding regions

Question 12

Explain how and why HLA polymorphism is good and bad

Answer 12

With increased MHC variants (alleles), it is beneficial for the population and individual to be able to destroy pathogens. It is a problem for tissue transplantation because it’s then difficult to find a perfect match

Question 13

Explain differences between MHC class I and II antigen processing and presentation

Answer 13

MHC class I:
Ag origin: intracellular proteins = endogenous
Cytosolic processing pathway
Presentation to CD8 T cells (CTLs)
MHC class II:
Ag origin: extracellular proteins = exogenous
Endocytic processing pathway
Presentation on CD4 Th cells (helper cells)

Question 14

Explain the cytosolic processing pathway

Answer 14

For endogenous Ags/intracellular pathogens, like viruses
Cellular proteins (viruses) are normally degraded by proteasomes - protein fragments are actively transported by Tap1 and Tap2 molecules from cytosol to the endoplasmic reticulum
Once in the ER, the peptide is loaded on the MHC class I molecules, which are then released in vesicles and transported to the cell surface for presentation
Class I molecules will NOT exit ER without a peptide
This process occurs continuously, so most MHC class I molecules display normal, self peptides
Once presented on the surface, if it’s a virus or other pathogenic Ag, the cell will be killed

Question 15

Explain the endocytic processing pathway

Answer 15

For exogenous (extracellular) Ags 
1. Endocytosed material fuses with lysosome to create a phagolysosome for degradation
2. MHC Class II synthesized by passing through ER and gogi to get to cell surface 
3. In ER, MHC Class II complexed with invariant chain, which blocks Ag binding site 
4. Once in vesicle, invariant chain is cleaved, leaving CLIP fragment, which stays bound to the peptide binding site to prevent degradation and autoimmunity
5. vesicle fuses with phagolysosome
6. CLIP is exchanged for peptide derived from exogenous Ag
7. Complex goes to surface, displays MHC class II bound to peptide to CD4 Th
MHC class II will not go to surface w/o loaded peptide so will have self derived peptides when no Ags

Question 16

What is the physiological significance of having 2 pathways?

Answer 16

1. Compartmentalization of pathways induces appropriate effector functions for antigens with different origins
2. Endogenous Ags presented to CTLs reflect “red flags” of inner health
3. Exogenous Ags to Th: infectious agent in tissues, stimulate B cells to make Abs and activate phagocytes