Module 6: Cellular Response Flashcards
What are the 3 signals required for T cell activation?
1) Antigen-specific TCR engagement
2) Costimulatory interactions
3) Cytokines directing differentiation
What are the 2 main positive costimulatory receptors on T cells?
1) ICOS which binds ICOS-L on B cells, some APCs, and T cells
2) CD28 which binds B7 on APCs
What is the activity of CD28 costimulatory receptor on T cells?
Responsible for activation of naive T cells
What is the activity of ICOS costimulatory receptor on T cells?
1) Maintenance of activity of differentiated T cells
2) Essential in development and activation of follicular helper T cells
What are the 3 main negative costimulatory receptors on T cells?
1) CTLA-4 which binds B7 on APCs
2) PD-1 which binds PD-L on APCs, some T and B cells, and tumor cells
3) BTLA which binds HVEM on some APCs, T and B cells
What is the activity of CTLA-4 costimulatory receptor on T cells?
Maintaining peripheral T-cell tolerance, reducing inflammation, contracting T-cell pool after infection clearance
What is the activity of PD-1 and BTLA costimulatory receptors on T cells?
Regulation of Treg differentiation
Describe the structure of TCR
1) Composed of alpha chain and beta chain
2) Variable regions of alpha and beta chain make up the 3 CDRs (V segment = CDR1-2, D and J segment = CDR3)
3) Constant region contains transmembrane domains
What is special about γ/δ TCRs?
1) Only double negative T cells (CD4-/CD8-) express this receptor
2) Can recognize antigens without MHC
Describe the MHC I structure
1) Composed of an alpha chain in a noncovalent complex with a nonpolymorphic B2-microglobulin
2) The alpha chain has 3 external domains and 1 transmembrane domain
3) The B2-microglobulin allows for expression of molecule on the surface
4) The α1 and α2 domains form the cleft region
Describe the MHC II structure
1) Composed of 2 polymorphic chains (alpha and beta)
2) The α1 and β1 domains form the cleft region
What are the structural similarities of the 2 MHC classes?
1) Peptide-binding cleft
2) Transmembrane region
3) Cytoplasmic region
4) Nonpolymorphic Ig-like region that binds T cell coreceptors (CD4 or CD8)
Describe MHC-peptide interactions for MHC I molecules
1) Peptides presented are from endogenous proteins
2) Peptide-binding groove is closed at both ends, therefore can only hold peptides 8-10 AAs long
3) Anchor residues exist at both ends of the peptide for MHC interaction
4) Peptide forms a bulge in the middle
Describe MHC-peptide interactions for MHC II molecules
1) Peptides presented are derived from exogenous proteins
2) Peptide-binding groove is open at both ends, therefore can accommodate peptide 13-18 AAs long
3) Conserved residues are distributed along the length of the peptide
4) Motifs are less clear in MHC II molecules than MHC I
5) Pockets are more permissive in MHC II molecules
What are motifs?
Motifs are common sequences on a peptide that binds MHC
How is binding specificities for peptides determined on MHC molecules?
Some polymorphic residues on MHC determine specificity by forming pockets that interact with anchor residues on the peptide, while other polymorphic residues form structures recognized by T cells
What are polymorphic residues?
AAs that vary between individuals
What are class III MHC molecules
1) Complement and inflammatory proteins, those of which that do not present antigens to T cells
2) Diverse set of proteins that have little polymorphism and no structural/functional similarity to MHC I or II
What is the MHC (HLA) locus?
1) Tightly linked cluster of MHC genes, coding for class I (the alpha chain), class II (the alpha and beta chain), and class III molecules
2) Located on chromosome 6 in humans
What are the genes associated with class I MHC molecules?
HLA-A, HLA-B, and HLA-C - all encode for 3 different class I molecules with the same name
What are the loci associated with class II MHC molecules?
HLA-DP, HLA-DQ, and HLA-DR - each loci has genes coding for alpha and beta chains
How is MHC diversity generated?
1) Both MHC I and MHC II exhibit polymorphism (many alleles for a single gene), differences typically clustered within groove sites
2) MHC region is polygenic (influenced by 2+ genes)
3) Allelic forms of MHC genes are inherited in linked groups called haplotypes, and haplotypes from parents are co-dominantly expressed in offspring
Why is MHC diversity so important?
1) Increases the capacity of cells to present a wide variety of antigens
2) Different capabilities for presenting antigens may dictate the strength of the immune response (i.e., can influence disease and allergy susceptibility)
Why is MHC diversity problematic?
Non-matching MHC patterns between donors and recipients for transplantation will result in transplant rejection
