MHC Flashcards
1
Q
MHC molecules
A
- peptide antigens displayed by MHC class 1/2 molecules
- each class is structurally similar with the peptide binding groove
2
Q
MHC class 1
A
- membrane bound heavy (alpha) chains (3 of them) and B2 microglobulin
- a1/a2 domains of heavy chain similar and form the binding site
- a3 domain binds CD8
3
Q
MHC class 2
A
- membrane bound alpha chain and beta chain
- each chain has two extracellular domains: a1/B1 form binding site
- B2 domain binds CD4
4
Q
CD4/CD8 accessory molecules
A
- direct binding of T cells to class 2 and class 1 MHC
- class 1 binds only CD8 and class 2 binds only CD4
- TCR binds the complex of MHC and peptide antigen: binds both molecules
5
Q
Peptide Binding
A
- peptides bound by hydrogen bonds and ionic interactions
- base of the binding groove is a B sheet and 2 helices on the outside
- Class 1: peptide bound in pockets at end of groove (ends closed and peptide bound at end pockets)
- Class 2: peptide bound along its length (groove open for binding down it)
6
Q
Compare class 1 and 2 binding
A
Class 1
- peptide binding domain is a1/2
- cleft is closed at both ends
- binds 8-10 long peptides
- anchor residues at both ends of peptide: generally hydrophobic carboxyl-terminal anchor
- middle of peptide not bound that arches up away from MHC molecule
Class 2
- peptide binding domain is a1/B1
- cleft is open at both ends
- binds 13-18 long peptides
- anchor residues distributed along peptide
- peptide held at constant elevation above MHC cleft floor
7
Q
Peptide Sources
A
MHC class 1:
- intracellular antigen processed to peptides in proteasome
- transporting to ER
- peptide binding to MHC class 1 and presented at surface
MHC class 2:
- extracellular antigen endocytosed and processed in phagolysosome
- MHC class 2 moves through golgi before binding and presentation of peptide
8
Q
Proteasome
A
- cytosolic proteins degraded in proteasome
- constitutive proteasome: degrades cell components from stress and damage
- immuno proteasome: found after cytokine activation
- infection alters the proteasome structure (induced by IFNy)
- new catalytic subunits are expressed to increase cleavage after hydrophobic residues to increase the peptide number with C terminal hydrophobic residues that bind better to MHC class 1 proteins
- new cap structure accelerates release of peptides from proteasome
9
Q
Transporter for Antigen Processsing
A
- cytosolic proteins degraded in proteasome and transported into ER via the TAP
- peptide fragments pass through the TAP protein in ER membrane into the ER
- happens constituitively so the cell is always presenting peptides to send a signal about the state of the cell
10
Q
Peptide Loading Complex
A
- promotes assembly of peptides onto class 1 in Er
1. class 1 heavy chain stabilised by calnexin chaperone until B2 microglobulin binding
2. calnexin released and heterodimer of class 1 heavy chain and B2m forms loading complex
3. peptide delivered by TAP binds to heavy chain to form mature MHC
4. class 1 molecule dissociates from loading complex and is exported from ER
11
Q
Endoplasmic reticulum aminopeptidase
A
- peptide trimmed by ERAP to ensure good fit
- peptide editing
- loading is indiscriminate and peptide may be too long
- cleaves from N terminal to fit better into groove
- occurs inside the ER
12
Q
Extracellular Peptide
A
- taken up by APCs and degraded to peptides in acidified endosomes
- in early endosomes the pH is neutral but acidification activates proteases
- vesicle fuses with vesicles containing MHC class 2
13
Q
Class 2 MHC Binding
A
- class 2 molecules prevented from binding peptides in ER until they reach endocytic vesicles
1. invariant chain binds to MHC class 2 molecules and transports them to MHC compartment containing proteases
2. invariant chain cleaved to the CLIP short peptide
3. HLA-DM binds to class 2 MHC to induce conformational change to displace CLIP and facilitate peptide binding
4. tight binding displaces HLA-DM and class 2 MHC moves to plasma membrane - this minimises binding to self
14
Q
Cross presentation
A
- allows extracellular antigens to be presented by class 1
- rare usually (seen in hepatitis C viral infection)
- macrophages thought to phagocytose infected hepatocytes then the complex is trafficked to surface of the antigens escape the vesicle and get processed
15
Q
T cell receptor
A
- binds both peptide and MHC molecule
- TCR Va chain and VB domains each have 3 CDRs
- similar interaction when binding class 1/peptide and class 2 peptide complex
- CD3 loops bind peptide and CDR1 and 2 bind MHC
16
Q
MHC:peptide:TCR Complex
A
- 8 amino acid peptide shown in yellow
- long axis of TCR binds diagonally across peptide binding groove
- a chain CDR3 and B chain CDR3 bind peptide and rest binds the MHC
17
Q
MHC Tissue distribution
A
- class 1 expressed on most nucleated cells
- class 2 expressed on APCs
- expression levels influenced by cytokines (induce higher expression levels)
- activated T cells express class 2 (resting T cells do not)
- microglial cells express class 2
18
Q
MHC class 1 vs class 2
A
- MHC class 1 and 2 proteins differ in function and extent of polymorphism
- great variation between the population
Class 1 isotypes: - HLA-A, B, C highly polymorphic and present antigen to CD8 T cells
- HLA-E and G oligomorphic
- HLA-F has a single isotype
Class 2: - HLA-DM and DO : few isotypes and regulate peptide loading onto class 2 molecules
19
Q
MHC gene clusters
A
- specific gene clusters associated with antigen processing and presentation
- this is how immune transplants work : system recognises class 1 MHC on the donor tissue
- MHC complex contains multiple loci coding for class 1, 2, 3 proteins
- class 1 loci code for MHC class 1 heavy chains
- class 2 loci code for MHC class 2 a/B chains
- class 3 loci code for other proteins
20
Q
MHC polymorphoism
A
- some MHC genes highly polymorphic
- code for class 1 and class 2 proteins presenting antigen
- numerous genetic variants (alleles) exist in the human population each binding different types of peptides
- genes do not undergo rearrangement
- presence of multiple genes and alleles confer an ability to bind many peptides
- each person has 2 sets of MHC alleles expressed from each chromosome
- ability of a person to mount a immune response to an antigen is determined by MHC haplotype
21
Q
Variation in Binding Site
A
- variation in MHC allotypes is concentrated at antigen binding sites
- evolution favours this natural selection
- variability in class one a helices and floor and class two is the same
- class MHC 1 peptides have conserved residues at end each specific for each isoform (common patterns in the peptide binding motifs)
eg. L/R at site 2
22
Q
MHC restriction
A
- T cell recognition of antigens is MHC restricted
- TCR recognises antigen and MHC protein: needs both to be present
- TCR is specific for complex of peptide and specific class 1 isotype
- cannot bind same peptide presented by different isotype or different peptide presented by same isotype
23
Q
Selective pressure for diversity
A
- infectious disease is pressure for diversity
- epidemics of new diseases means individuals with specific haplotypes survive better
- heterozygosity is advantageous
24
Q
New MHC alleles
A
- interallelic conversion: recombination between alleles of same gene
- gene conversion: alleles of different genes
- may result in insertion of small segment introducing new amino acids into the binding site
- MHC also hotspot for mutation
25
Q
Autoimmune disease
A
- certain MHC alleles associated with increased risk of autoimmune disease
- loss of T cell tolerance to self peptide unerlies this
- AI disease triggered by infection : cross reactivity between self and pathogen antigen
- antigen sequence can be similar to the self peptide
- upregulation of class 2 MHC on non-APC can potentially present self peptides
