Download Notes on the MHC

Immunology: Role of the MHC in the Immune Response (Sundick)
MHC COMPLEX: MAJOR HISTOCOMPATABILITY COMPLEX
 Basics/History:
T cells only recognize peptide in association with self-MHC (will not bind free peptide)
MHC genes first recognized as important for tissue rejection; T cells play the major role in the
rejection of foreign tissue as they react with foreign MHC molecules on it
 MHC Genes and Products:
Human Leukocyte Antigen (HLA) Genes: subset of genes in the MHC region that encode the antigen
presenting proteins; separated into 2 classes:
o HLA Class I: HLA-A, HLA-B, HLA-C; encode MHC class I receptors
o HLA Class II: HLA-DP, HLA-DQ, HLA-DR; encode MHC class II receptors
 MHC Polymorphism and Codominant Expression:
MHC class I and II (genes located on chromosome 6) are codminantly expressed
Example:
o Father’s Alleles: A1, B6, C29, DP15, DQ23, DR4
o Mother’s Alleles: A2, B4, C29, DP14, DQ22, DR17
o Child: A1,2; B4,6; C29; DP14,15; DQ22,23; DR4,17
 Heterozygous for A, B, DP, DQ and DR
 Homozygous for C
Result of Child’s Phenotype:
o All nucleated cells will have the A,B and C alleles listed above
o All APCs will have the A,B, C, DP, DQ, and DR alleles listed above
Note: additional phenotypes are also possible and can be expressed for MHC class II; this is because
some of the alpha and beta chain pairings can occur between loci
o Example: DRα chain + DPβ chain
 MHC Haplotype:
The MHC is on a single chromosome (6), and therefore you inherit the complex as a single unit called
the MHC haplotype
Any of your siblings have a 25% chance of inheriting the same 2 chromosome 6’s, resulting in
identical MHC
Note: you would still differ at minor histocompatability loci that are encoded for by other cs
 Diversity of MHC Molecules:
Diversity is critical to safeguarding a species in order to have a repertoire diverse enough to respond
to all potential pathogens and mutations of pathogens
Some MHC alleles are associated with a high incidence of autoimmunity and allergy and a low
response to pathogens
 Other Genes Within the MHC Region:
MHC Class III: serum complement proteins, cytokines, heat shock proteins
Addition MHC Class I and II: facilitate binding of peptide to MHC (HLA-DM, Tap-1, Tap-2, proteosome
protens)
CLASS I MHC:
 Expression: constitutively on all nucleated cells, including APCs
 Encoding:
Coded by 3 separate loci (A,B,C), with each locus coding for an α chain only (highly polymorphic)
Alpha chain combines with a nonpolymorphic/invariant chain, β2-microglobulin
Each cell will simultaneously express HLA-A, HLA-B and HLA-C
 Structure:
Alpha1 and Alpha2 domains interact with peptide (closed binding groove; 8-9 aa)
Alpha3 domain interacts with CD8 (on cytotoxic T cell)
 Function: to present foreign peptide antigens to CD8+ T cells (endogenous Ag)
Infectious agent (virus, bacteria, parasite) penetrates the cell in order to replicate
-
Undergoes protein synthesis, and some protein is degraded by proteosome
Peptides from proteosome transported to ER by TAP-1 and TAP-2 transporters
If peptide has sufficient binding affinity for the MHC molecule (immuodominant epitope), it becomes
associated with MHC class I
MHC class I + foreign peptide move to the surface of the infected cell to present to CD8+ T cells
CLASS II MHC:
 Expression: constitutively only on APCs (dendritic cells, macrophages, and B cells) and thymic epithelial
cells; can also be induced on fibroblasts and endothelial cells
 Encoding:
Coded by 3 separate loci (DP, DQ, DR), with each locus having an A and B gene encoding for an α and
β chain, respectively (chains are highly polymorphic)
An APC will simultaneously express HLA-DP, HLA-DQ and HLA-DR; this enhances the likelihood of
binding to and presenting foreign peptide to T cells
 Structure:
Alpha1 and Beta1 domains interact with peptide (open binding groove; 12-20 aa)
Beta2 domain interacts with CD4 (on helper T cell)
 Function: to present foreign peptide antigens to CD4+ T cells (exogenous Ag)
Infectious agent is phagocytosed by an APC and enclosed in an intracellular vesicle
Vesicle fuses with an endosome or lysosome, and proteins are digested into peptides
Vesicle of degraded peptides fuses with vesicle containing newly formed MHC class II with CLIP
attached
If peptide has sufficient binding affinity for the MHC molecule (immuodominant epitope), it binds
MHC class II in exchange for CLIP, a process mediated by HLA-DM
o CLIP: MHC class II is assembled in the ER/Golgi with CD74 attached
 CD74 (invariant chain) acts as both a chaperone and an inhibitor of endogenous
protein binding
 When the Golgi releases the vesicle with the newly formed MHC, CD74 is degraded
down to CLIP, which is eventually replaced with foreign Ag
MHC class II + foreign peptide move to the surface of the infected cell to present to CD4+ T cells
OTHER PATHWAYS OF ANTIGEN PROCESSING AND PRESENTATION:
 Peptides can bind MHC at the cell surface
 APCs can take up exogenous protein and process them both in the class I and class II pathway (will be
presented by both); this is called cross-priming
 Superantigens: proteins that binds both MHC class II and the germline configuration of the TCR Vβ
simultaneously
These areas that it binds on MHC II and the TCR are highly conserved and therefore, they can interact
with a large percentage of T cells (up to 10%)
Leads to overactivation of T cells
SELF PEPTIDES AND T CELLS:
 Why don’t self peptides activate T cells?
Many self reactive T cells eliminated in thymus
Self-peptides do not activate T cells in the absence of costimulatory signals