Module 6: Cellular Response

Question 1

What are the 3 signals required for T cell activation?

Answer 1

1) Antigen-specific TCR engagement
2) Costimulatory interactions
3) Cytokines directing differentiation

Question 2

What are the 2 main positive costimulatory receptors on T cells?

Answer 2

1) ICOS which binds ICOS-L on B cells, some APCs, and T cells
2) CD28 which binds B7 on APCs

Question 3

What is the activity of CD28 costimulatory receptor on T cells?

Answer 3

Responsible for activation of naive T cells

Question 4

What is the activity of ICOS costimulatory receptor on T cells?

Answer 4

1) Maintenance of activity of differentiated T cells
2) Essential in development and activation of follicular helper T cells

Question 5

What are the 3 main negative costimulatory receptors on T cells?

Answer 5

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

Question 6

What is the activity of CTLA-4 costimulatory receptor on T cells?

Answer 6

Maintaining peripheral T-cell tolerance, reducing inflammation, contracting T-cell pool after infection clearance

Question 7

What is the activity of PD-1 and BTLA costimulatory receptors on T cells?

Answer 7

Regulation of Treg differentiation

Question 8

Describe the structure of TCR

Answer 8

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

Question 9

What is special about γ/δ TCRs?

Answer 9

1) Only double negative T cells (CD4-/CD8-) express this receptor
2) Can recognize antigens without MHC

Question 10

Describe the MHC I structure

Answer 10

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

Question 11

Describe the MHC II structure

Answer 11

1) Composed of 2 polymorphic chains (alpha and beta)
2) The α1 and β1 domains form the cleft region

Question 12

What are the structural similarities of the 2 MHC classes?

Answer 12

1) Peptide-binding cleft
2) Transmembrane region
3) Cytoplasmic region
4) Nonpolymorphic Ig-like region that binds T cell coreceptors (CD4 or CD8)

Question 13

Describe MHC-peptide interactions for MHC I molecules

Answer 13

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

Question 14

Describe MHC-peptide interactions for MHC II molecules

Answer 14

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

Question 15

What are motifs?

Answer 15

Motifs are common sequences on a peptide that binds MHC

Question 16

How is binding specificities for peptides determined on MHC molecules?

Answer 16

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

Question 17

What are polymorphic residues?

Answer 17

AAs that vary between individuals

Question 18

What are class III MHC molecules

Answer 18

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

Question 19

What is the MHC (HLA) locus?

Answer 19

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

Question 20

What are the genes associated with class I MHC molecules?

Answer 20

HLA-A, HLA-B, and HLA-C - all encode for 3 different class I molecules with the same name

Question 21

What are the loci associated with class II MHC molecules?

Answer 21

HLA-DP, HLA-DQ, and HLA-DR - each loci has genes coding for alpha and beta chains

Question 22

How is MHC diversity generated?

Answer 22

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

Question 23

Why is MHC diversity so important?

Answer 23

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)

Question 24

Why is MHC diversity problematic?

Answer 24

Non-matching MHC patterns between donors and recipients for transplantation will result in transplant rejection

Question 25

What are 4 different factors that can change MHC expression?

Answer 25

1) Genetic regulatory components (promoters drive up transcription during infection)
2) Viral infection may result in limited MHC I expression to avoid CD8+ T cells
3) Cytokines can drive up expression (IFN)
4) Corticosteroids and prostaglandins can downregulate expression

Question 26

What is the requirement for T cells to recognize a MHC-antigen complex?

Answer 26

The MHC haplotype of the presenting cell must match the haplotype of the T cell

Question 27

What does syngenic mean?

Answer 27

Identical at all genetic loci

Question 28

What does congenic mean?

Answer 28

Genetically identical at all loci except at one single genetic region

Question 29

What is the mouse equivalent of MHC I and II genes?

Answer 29

1) MHC I - 3 types encoded for by H2-K, H2-D, H2-L
2) MHC II - 2 loci, I-A and I-E