4. Antigen Processing and Presentation Flashcards
What is MHC restriction?
- T cell co-recognition of a foreign peptide/ self MHC molecule
> particular MHC allele restricts ability of T cells to recognize antigens
Cytosolic pathogens bind to what MHC class?
MHC class I
- present antigen to effector CD8 T cells
Intravesicular pathogens bind to what MHC class?
MHC class II
- present antigen to effector CD4 T cells
Extracellular pathogens bind to what MHC class?
MHC class II
- present antigen to effector CD4 T cells
> activation of B cells to secrete Ig to eliminate extracellular pathogens
How can extracellular antigens be displayed on MHC I?
(normally on MHC class II)
- cross-presentation of extracellular antigens on MHC class I molecules by DCs
> translocation of proteins from phagolysosome > cytosol for degradation by proteasome > resultant peptides passed into ER where they load onto MHC I
> direct transport of antigens from phagolysosome > vesicular loading compartment where they load onto MHC I (no passage through cytosol)
How can extracellular antigens be cross-presented on MHC class I molecules by DCs?
- translocation of proteins from phagolysosome > cytosol for degradation by proteasome > resultant peptides passed into ER where they load onto MHC I
- direct transport of antigens from phagolysosome > vesicular loading compartment where they load onto MHC I (no passage through cytosol)
How can cytosolic antigens be displayed on MHC class II?
(normally on MHC class I)
- autophagy pathways can deliver cytosolic antigens for presentation by MHC class II molecules
- portions of cytoplasm are taken into autophagosomes
> specialized vesicles fused with endocytic vesicles/ lysosomes - contents catabolized > peptides can be bound to MHC II
What cells express MHC class I molecules?
- all nucleated cells
- not RBCs (unnucleated)
- most highly expressed in hematopoietic cells
What kind of protein is MHC molecule?
- member of immunoglobulin superfamily
> has immunoglobulin domains
Where is the peptide-binding groove formed in both MHC class I/ MHC class II molecules?
- by the membrane-distal domains
- MHC class I > α1/ α2 domains
- MHC class II > α1/ β1 domains
Where is the immunoglobulin domain structure in MHC class I/ MHC class II molecules?
- in the membrane-proximal domains
How are peptides bound differently in MHC class I/ II?
- MHC class I > peptide bound in elongated conformation/ both ends tightly bound at either end of the cleft (closed at both ends)
- MHC class II > peptide bound in elongated conformation/ ends of peptide not tightly bound > peptide extends beyond cleft (open at both ends)
What are the structural characteristics of MHC class I?
- present antigens to CD8+ T cells
- composed of 4 domains: α1/ α2/ α3/ β2 microglobulin
- α3/ β2 microglobulin > proximal/ fold similar to Igs
- α1/ α2 domains > antigen binding groove/ highly polymorphic
What are the structural characteristics of MHC class II?
- present primarily on APCs > present antigens to CD4+ T cells
- composed of 2 separate chains: α/ β
- each MHC II chain is folded into 2 domains > α1 and α2/ β1 and β2
- α1/ β1 domains form antigen binding groove
- β chain is polymorphic (especially β1 domain)
How do MHC class I molecules interact with peptides?
> bound by their ends
- series of hydrogen bonds/ ionic interactions at each end
- AA that form these bonds are common to all MHC class I molecules
How do peptides bind to MHC class I molecules?
- through structurally related anchor residues
- anchor residues differ for peptides that bind different alleles of MHC class I
- anchor residues are similar for all peptides that bind to same MHC molecule
- anchor residues that bind a particular MHC do not have to be identical but are always related (same chemical features)
- peptides also bind MHC I through amino/ carboxyl termini
What are anchor residues?
- AA’s in peptides that interact with MHC molecule
- anchor residues differ for peptides that bind different alleles of MHC class I
- anchor residues are similar for all peptides that bind to same MHC molecule
- anchor residues that bind a particular MHC do not have to be identical but are always related (same chemical features)
How long are peptides that bind to MHC 1?
- 8-10 AA
- have 2/3 anchor residues
How long are peptides that bind to MHC II?
- variable length of peptides (13-18 AA residues)
- have 4 anchor residues
- naming convention > first anchor residue is residue 1
How do peptides bind to MHC class II molecules?
- series of hydrogen bonds distributed along length of protein in the binding groove
What is MHC called in humans/ mice?
- humans > HLA
- mice > H2
What were MHC antigens called when first discovered?
histocompatibility antigens
What are the different human MHC I/ MHC II molecules? (HLA)
- MHC I > A/ B/ C
- MHC II > DP/ DQ/ DR
What are the different mice MHC I/ MHC II molecules? (H2)
- MHC I > K/ D
- MHC II > A/ E
What is polygeny?
- MHC region contains multiple genetic loci encoding proteins with the same function
- ensures that each individual produces different MHC molecules
> ex- HLA-A/B/C can all present peptides to CD8+ T cells
> ex- HLA-DP/DQ/DR can all present peptides to CD4+ T cells
What is polymorphism?
- each gene in MHC locus has several alleles within population
> ensures diversity in MHC gene expression in population as a whole
What is co-dominant expression?
- alleles from each haplotype are expressed in any 1 individual
> ex- AB blood type/ MHC molecules
What contributes to the diversity of MHC molecules expressed by an individual/ population?
- polygeny > presence of different related genes with similar functions > ensures each individual produces a # of different MHC molecules
- polymorphism > polymorphism of MHC genes ensures diversity in MHC gene expression in the population
Where does allelic variation of MHC molecules predominantly occur?
- within peptide-binding region
How are MHC molecules co-dominantly expressed?
- genes within MHC locus have codominant expression
> both maternal/ paternal gene products expressed at same time
Where does assembly/ stabilization of MHC class I molecules occur?
RER
- TAP (transporter associated with antigen processing) transports peptides from cytosol > RER to associate with MHC class I
What is the endogenous pathway for antigen presentation by MHC class I molecules?
- endogenous antigens in cytosol degraded by proteasome > converts protein into smaller peptides
- peptide transported to RER via TAP
- MHC I binds to peptide > MHC I-peptide complex transported from RER to plasma membrane
What is the exogenous pathway for antigen presentation by MHC class II molecules?
- receptor-mediated endocytosis of extracellular antigens
- extracellular antigens engulfed into endocytic compartments > degraded by acidic pH lysosomal/ endosomal enzymes
- peptide associates with MHC class II in endocytic compartment
> MHC II-peptide complex transported to plasma membrane
What is cross-presentation?
- dendritic cells cross-present exogenous antigen via MHC I
> critical for activation of naive CD8+ T cells
What are superantigens?
- antigens recognized by T cells without being processed into peptides captured by MHC molecules
- produced by many different pathogens
- responses they provoke are helpful to pathogen
> systemic toxicity/ suppression of adaptive immune response
What is the determinant selection model?
- different MHC class II molecules differ in ability to bind particular processed antigens
> some peptides may be more critical to eliminate pathogens than others
> ability of organism to present these peptides would give them an advantage
What is the holes in the repertoire model?
- T cells with receptors that recognize certain foreign antigens that closely resemble self-antigens may be eliminated during T cell development > leaves organism without these receptors
