MHC, Antigen Processing & Presentation - Binder

Question 1

How do Ig’s and TCR ligands differ?

Answer 1

Ig’s can bind to a large variety of antigen (lipids, carbohydrates, peptides, etc.). TCR’s in contrast only bind peptides presented on MHC molecules.

Question 2

Describe dendritic cell maturation.

Answer 2

DC’s in the tissues upon recognition of antigen will mature, releasing cytokines and migrate to the lymphatic tissues to engage T-cells and B-cells.

Question 3

Describe the general structure of MHC-I molecule.

Answer 3

In the upper portion there is a peptide binding cleft where antigen is bound which is composed of alpha 1,2 chains. In the lower portion, the alpha 3 chain and non-HLA associated beta-2 chain provide structural support for CD8 binding. There is only 1 transmembrane region.

Question 4

Describe the general structure of the MHC-II molecule.

Answer 4

In the upper portion there is a peptide binding cleft made up of an alpha-1 chain and beta-1 chain. The lower portion is made up of an alpha-2 and beta-2 chain. There are 2 transmembrane regions.

Question 5

What does co-dominant expression of MHC mean?

Answer 5

Both alleles from mom and dad for MHC are expressed at the same time. This is a source of diversity for MHC molecules.

Question 6

How many types of MHC-I molecules can be expressed by any given cell?

Answer 6

6 because they all have the same beta chain and there are 3 alleles from each parent (6 total).

Question 7

What does it mean that MHC is polymorphic?

Answer 7

Each individual has different MHC expression which ensures individuals are able to respond to different pathogens.

Question 8

Which cells express MHC-II?

Answer 8

Dendritic cells, macrophages, B-cells. They all express MHC-I as well.

Question 9

Which cells express MHC-I?

Answer 9

All nucleated cells.

Question 10

Describe how peptides are bound to MHC-I binding grooves? How large are these peptides?

Answer 10

Peptides are sandwiched between alpha chains and are only up to 12 AAs in length.

Question 11

Describe how peptides are bound to MHC-II binding grooves? How large are these peptides?

Answer 11

Peptides are sandwiched between the alpha 1 and beta 1 chains. They can be much longer than the peptides on MHC-I.

Question 12

How is the peptide interaction with the MHC binding cleft stabilized? What happens if its mutated?

Answer 12

Anchor residues engage MHC residues deep in the binding cleft stabilizing the peptide to MHC. If these residues are mutated, they likely won’t bind to MHC.

Question 13

How is the peptide interaction with TCRs affected by mutation in the peptide residues on the surface?

Answer 13

Peptide residues sticking out of the MHC peptide binding cleft will engage with TCRs. If this region is mutated, they will either engage a different TCR or none altogether.

Question 14

How many peptides can MHC bind at one time?

Answer 14

Only one. This means that T-cells respond to only a single unique peptide bound to a specific MHC.

Question 15

What is the specificity of MHC?

Answer 15

MHCs can bind many different peptides, only one at a time.

Question 16

What does the slow-off rate of MHC mean and what does it imply?

Answer 16

MHC-peptide complexes are very stable which allows ample time for T-cells to recognize and bind MHC-peptides.

Question 17

Do MHCs present self-peptide?

Answer 17

Yes, in fact they mostly present self-peptide. In the case of an infection, only a fraction of MHC molecules on a cell surface will present pathogen-derived peptide.

Question 18

What macromolecules do MHC-restricted T-cells recognize?

Answer 18

Only peptide.

Question 19

All membrane bound proteins inside the cell interact with ___. This is the ___ pathway.

Answer 19

All membrane-bound proteins interact with the ER as part of the secretory pathway.

Question 20

When is MHC expressed?

Answer 20

All the time. New MHC molecules are being secreted to the cell surface all the time. When not bound to peptide, they are degraded quickly.

Question 21

Describe the process of MHC-II processing and antigen loading.

Answer 21

Dendritic cells or macrophages phagocytose pathogen. Pathogen peptides are degraded in endocytic vesicles. Simultaneously, MHC-II molecules in the ER bound for the cell-surface are plugged with an invariant chain to prevent binding of ER-derived self peptides. MHC-II vesicles fuse with endocytic vesicles, binding pathogen-derived peptide to MHC-II which is trafficked to the cell-surface.

Question 22

Describe the process of MHC-I processing and antigen presentation.

Answer 22

Infected cells are making pathogen-derived peptides in the cytosol. Some of these are trafficked to the ER where they are bound to MHC-I molecules. MHC-I molecules bound to these peptides are trafficked to the surface. There is no invariant chain because you need peptides in the ER to bind to MHC-I.

Question 23

Which T-cells engage with MHC class I?

Answer 23

CD8+ T-cells

Question 24

Which T-cells engage with MHC class II?

Answer 24

CD4+ T-cells

Question 25

What is the source of peptides bound to MHC-I?

Answer 25

Pathogen-derived proteins being made in the cytosol and transported to the ER.

Question 26

What is the source of peptides bound to MHC-II?

Answer 26

Phagocytosed pathogens being degraded and transported to endocytic vesicles. Peptides containing vesicles fuse with MHC-II containing vesicles.

Question 27

What are the enzymes responsible for peptide generation in MHC I and II pathways?

Answer 27

In MHC-I bound peptides, cytosolic proteasomes process peptides. In MHC-II, endosomal and lysosomal proteases process peptides.

Question 28

What is the site of peptide loading for MHC I and MHC II?

Answer 28

MHC I peptide loading occurs in the ER. MHC II peptide loading occurs in vesicles.

Question 29

What is the function of DM and TAP.

Answer 29

In MHC II antigen loading, DM removes the invariant chain to expose MHC II to peptide. In MHC I antigen loading, TAP transports peptides degraded by cytosolic proteasomes to the ER.

Question 30

What is cross-presentation?

Answer 30

When peptides that should be presented by MHC-II get presented by MHC-I.

Question 31

What is the function of ERAP?

Answer 31

ERAP is an aminopeptidase which cleaves peptides one at a time to the correct length for MHC-I loading.

Question 32

How does MHC-II antigen recognition stimulate effector function?

Answer 32

CD4+ T-cells recognizing MHC I secrete cytokines to signal B-cell antibody secretion and phagocyte activation

Question 33

How does MHC-I antigen recognition stimulate effector function?

Answer 33

CD8+ T-cells (killer T-cells) will kill infected cell.

Question 34

What is the role of MHC in thymic selection of T-cells?

Answer 34

If TCR interaction with self-presenting MHC in the thymus is too strong, or too weak, T-cell will undergo apoptosis.

Question 35

What is direct recognition and rejection

Answer 35

T-cells recognize foreign MHC from a donor graft regardless of peptide presented and kill the cell. Causes very acute rejection.

Question 36

What is indirect recognition and rejection?

Answer 36

Foreign donor MHC is taken up by recipient APC and presented to T-cells.

Question 37

How would you type an individual’s HLA expression? Which HLA genes are most important?

Answer 37

You can use antibodies or PCR. HLA A, B, C, and DR are considered.

Question 38

What causes such diversity in MHC in a species?

Answer 38

Polymorphisms

Question 39

How can viruses evade CD8+ T-cells?

Answer 39

They can block MHC-I peptide loading with proteins that can block or compete with TAP.

Question 40

How do tumors evade CD8+ T-cell destruction?

Answer 40

Tumor cells sometimes don’t express MHC-I

Question 41

What are NK cells role in tumor destruction?

Answer 41

Altered or absent MHC on cell surface are targets for NK cells