L6: Major Histocompatibility Complex Flashcards
What do T cells recognize?
Processed antigen fragments presented by MHC molecules
What do helper CD4+ T cells recognize?
Processed antigen fragments presented by MHC class II molecule
What do cytotoxic CD8+ T cells recognize?
Processed antigen fragments presented by MHC class I molecule
What gene complex encodes the MHC proteins in humans?
Human leukocyte antigen (HLA)
What loci is human MHC Class I encoded by?
Loci HLA-A, HLA-B, and HLA-C
What loci is human MHC Class II encoded by?
HLA-DR, DQ, and DP
What are some other genes mapped within the MHC region?
Factor B Complement proteins TAP1 and TAP2 Cytokine genes (such as TNF) Some non-classical MHC class I genes: HLA-E, HLA-F, and HLA-G
What are the 2 striking characteristics of the MHC system?
- Extremely polymorphic: at each of the loci, there are numerous alternative alleles
- These, as far as expression of HLA molecules on surface of cells that express them, will be co-dominantly expressed
What is the inheritance pattern of HLA?
Standard Mendelian segregation
Recombination can occur
In MHC Class I, which loci is most polymorphic?
B
In MHC Class II, which loci is most polymorphic?
DRB
Describe the general structure of MHC Class I molecules
Heavy α
chain that is non-covalently associated w/ small chain called β-2 microglobulin
What aspect of MHC class I molecules is invariant?
β-2 microglobulin
α3 domain
What forms the peptide binding cleft in MHC class I molecules?
α1 and α2 domains
Where on MHC class I does the receptor recognize it?
α3 domain
Describe the general structure of MHC class II
2 heavy chains: an α chain and a β chain
What forms the peptide binding cleft in MHC class II molecules?
α1 and β1 regions
At any given time, how many peptides can a peptide binding cleft bind?
1 peptide
What is the nature of the peptide-binding cleft of MHC class I molecules? Class II molecules?
Class I: closed at both ends
Class II: open at both ends
What is the general size of bound peptides of MHC class I molecules? Class II molecules?
Class I: 8 - 10 amino acids (9 is ideal)
Class II: 13 - 18 amino acids
What are the peptide motifs involved in bind to MHC class I molecule? Class II molecule?
Class I: Anchor residues at both ends of peptide; generally hydrophobic carboxyl-terminal anchor
Class II: Anchor residues distributed along the length of the peptide
What allows MHC class II molecules to bind larger peptides?
Peptide binding cleft is open
What has to be the same in all the peptides that can bind a specific MHC class I molecule?
The anchor residues must be the same for them to bind the same MHC class I molecule
What are the anchor residues of MHC class I molecules?
2 and 8 positions
What are the anchor residues of MHC class II molecules?
Anchor residues not so well defined
Where does allelic variation occur within MHC molecules?
In peptide binding pockets
For class I, variation is found in alpha 1 and apha 2 domains (alpha 3 is invariant)
For class II, variation is found mostly in beta 1 domain
How is T cell recognition of antigens restricted?
It is MHC restricted
T cell receptor has a specific recognition area that will bind self-MHC that some processed peptide
Both the peptide and the MHC molecule need to be correct for recognition to occur
Where are MHC class I molecules distributed (in humans)?
All nucleated cells
Platelets
Not on RBCs (which is fortuitous in blood transfusion)
Where are MHC class II molecules distributed (in humans)
Primarily on cells that can act as antigen-presenting cells
B cells
Macrophages
Dendritic cells
Activated T cells (human)
Are all cells that express class II molecules also going to express class I molecules?
Yes
Are all cells that express class I molecules going to express class II molecules?
Not necessarily
What is the exception to the rule of T cells only recognizing self-MHC w/ some foreign antigenic peptide attached to it?
T cell alloreactivity
T cell alloreactivity
Ability of T cell in culture dish or in vivo (in certain conditions) to recognize foreign, or non-self, MHC
Only time this could happen in vivo is in case of organ transplantation where organ is of different MHC than you are
Could also happen during a blood transfusion if WBCs are part of blood product that you receive
Or during pregnancy
This is the basis of what happens in graft rejection
What are the situations in which allogenic T cell reactivity occurs in vivo?
Organ transplant
Blood transfusion if WBCs are part of the blood product
During pregnancy
Superantigen
Don’t bind in the antigen binding groove
Bind on the outside of the antigen presenting cell
Many different T cells can bind to a self-MHC that has either a bacterial or viral superantigen that is attached to it
Why is high level of MHC polymorphism advantageous?
Most human MHC molecules are expressed at pretty low frequency since there are so many different ones that can bind different antigenic peptide
If there was limited expression of MHC, there would be limited binding of those viruses and thus there would be limited response
How is serological tissue typing done?
Use HLA molecules since they are expressed on WBCs and you can detect them serologically; have antibodies to almost all of the different alleles that are found
Take a donor cell and put it in a dish w/ an antibody to a certain HLA allele → if there is that HLA allele, there will be formation of antigen-antibody complex → add complement → cell membrane lysis if there is antigen-antibody complex → add dye → if there was membrane lysis, the dye is taken up by the cell → if dye was taken up, tells us that this cell expressed that HLA allele
MHC typing by PCR hydbridization
Same concept as serological testing, but more sensitive and quicker
Mixed lymphocyte reaction
To measure alloreactivity
What is the effect of HLA class I and class II matching on allograft survival?
If there are no mismatches at MHC class I and II molecules b/w recipient and donor, have much higher survival rate of graft
As you increase the # of mismatches, survival rate decreases
