Lecture 4 (Dustin) - MHC Presentation

Question 1

What does MHC stand for? What does it mean?

Answer 1

Major Histocompatibility Complex.

These are immunogenic alloantigen proteins on cell surface. Were discovered via research on organ transplants. Helps cells determine “self” vs “non-self” and induce an adaptive immune response

Question 2

What are the subunits of MHC class I?

suggest you look at the lecture slide picture

Answer 2

Alpha 1, 2 and 3 (alpha 3 has a transmembrane domain)
Beta2microglobulin
(heterodimers)

Question 3

What are the subunits of MHC class II?

Answer 3

Alpha 1 and 2, with a TM domain on alpha 2

Beta 1 and 2, with a TM domain on beta 2

Question 4

Which cells contain MHC class I?

Answer 4

All nucleated cells (no red blood cells)

Question 5

Which cells contain MHC class II?

Which cells recognize MHC class II?

Answer 5

Only professional antigen-presenting cells (APC’s) contain MHC class II

Th cells use their T cell receptor to recognize MHC class II in a complex with a presented antigen (“co-recognition”)

Question 6

What does HLA stand for?

Answer 6

Human Lymphocyte Antigen

Question 7

Which HLA's make up MHC class I?
And MHC class II?

Answer 7

MHC Class I = HLA-A, HLA-B, HLA-C

MHC Class II = HLA-DP, HLA-DR, HLA-DQ

Question 8

What are 4 things coded in the MHC III gene region (near the coding for MHC I and II)

Answer 8

MHC III region contains the things that make up C3 convertases (C4b, C4a, Factor B, C2)

Question 9

What does it mean that the MHC gene coding regions are both polygenic and polymorphic?

Answer 9

Several different genes with similar functions -> individual has many different MHC molecules (polygeny)

Within an individual and across the population, a great diversity of MHC molecules is possible with both MHC class I and II due to both polymorphism and polygeny

Question 10

What chromosome are the MHC encoding regions on? How are they inherited?

Answer 10

On chromosome 6 (“genetic hot spot”)

Co-dominantly inherited - both alleles of gene are co-expressed (from both mom and dad)

Question 11

What regions of MHC Class I and II provide the most genetic diversity?

Answer 11

HLA-B provides the most diversity of MHC Class I

HLA-DRB provides the most diversity with MHC Class II

Question 12

Can a single cell display just one type of MHC or many?

Answer 12

One cell can display a large array of MHCs.

All the somatic cells display the same HLA molecules. APC’s express both MHC class I and II HLA’s.

Question 13

Apart from the “traditional” APC’s like dendritic cells and macrophages, what are two other types of cells that have MHC class II?

Answer 13

B cells and epithelial cells of the thymus (for T cell maturation)

Question 14

How many amino acids are on an MHC class I peptide vs a MHC class II peptide?

Which one is “endogenous” and which one is “exogenous?”

Answer 14

MHC class I: 8-9 AA's, endogenous peptide
MHC class II: 11-25 AA's, exogenous "non-self" peptide

Question 15

Which MHC class is better at showing the cell has been infected by viruses or altered to a tumor cell?

Answer 15

MHC Class I: cytotoxic T cells notice the change of MHC class I due to DNA change (because it’s an endogenous peptide) and kill the cell

Question 16

What problems is MHC class II good at showing to the immune system?

Answer 16

Foreign antigens like bacterial peptides, parasites. APC’s phagocytose these things, process them, and show their peptides with MHC class II to Th cells.

Question 17

What are the two main pathways of receiving antigens?

Answer 17

1. Cytosol-derived (endogenous antigens) - tumor or viral antigens, also intracellular bacteria
2. endosome/lysozome-derived (exogenous antigens)

Question 18

How are MHC I generated?

Answer 18

A self or viral protein in the cytosol is cut into peptide fragments by a proteosome. rER produces a new MHC I molecule, which binds the peptide and moves to the cell surface (the MHC is never expressed without a peptide complex). Peptides need access to the ER in order to be loaded onto class I molecules.

Question 19

What is the TAP protein?

Answer 19

Transporter of Antigen Processing (TAP). It’s an ATP-dependent peptide transporter that brings peptides (prefers hydrophobic and >8 AA’s long) from the cytosol to the rER lumen and helps them bind in a complex with MHC I

Question 20

What is the role of the beta2 microglobulin in the MHC I complex?

Answer 20

Stabilizes MHC I for correct peptide binding (probably more to it than this…)

Question 21

What criteria do peptides have to have in order to fit into the MHC Class I cleft?

Answer 21

1. Right size: 8-9 AA’s long

2. Two anchoring residues: phenol rings (from Tyr and Phe) and hydrophobic methyl groups (from Leu, Val, Ile)

Question 22

Repeat from first lecture: what are the inhibiting and activating receptors to know for Natural Killer cells?

Answer 22

Inhibitory: NKG2A (the cell is A-OK!)
Activatory: NKG2D (D because the cell should die)

Remember NK cells kill ones without proper MHC class I identification

Question 23

What is there to know about HLA-E, F, and G from the lecture?

Answer 23

These are “non-classical” HLA’s, they’re less polymorphic, limited repertoire of peptides presented to T cells.

NKG2A recognizes them

Question 24

What are the 3 ways that phagocytes take up antigens? Which are the most effective?

Answer 24

1. Lectin receptors (least effective)
2. Fc gamma receptors (moderately effective)
3. Complement receptors (most effective)

Question 25

How do B cells take up antigens?

Answer 25

B cell receptors

Question 26

Which protein binds the MHC class II groove so that no other peptides can yet bind until they’re ready?

What removes this peptide?

Answer 26

CLIP: Class II-associated invariant chain peptide. Prevents the MHC Class II from binding endogenous peptides.

HLA-DM removes CLIP

Question 27

How does MHC Class II come into contact with exogenous peptides?

Answer 27

The rER and golgi produce lysosomes containing MHC II with CLIP occupying the binding site, and these fuse with endosomes of phagocytosed and degraded antigens. HLA-DM then both removes the CLIP peptide and coordinates the binding of exogenous peptides in CLIP’s spot.

Question 28

What is the role of the invariant chain (Ii) in MHC Class II maturation?

Answer 28

The Ii chain starts out as a long chain that localizes and stabilizes the MHC II molecule inside a lysosome. It includes the CLIP portion that occupies the MHC Class II binding site. Inside the lysosome, most of the Ii protein breaks apart, except for the CLIP portion.

Question 29

How do the antigen presentation goals of dendritic cells vs other phagocytes differ?

Answer 29

Dendritic cells carry the pathogen to the lymph node for naive T-cells to induce them to be activated/differentiated (priming)

B-cells and macrophages present the antigen to effector (not naive!) T-cells in order to get signals to facilitate their maturation

Question 30

What type of T cells recognize endogenous antigens vs exogenous antigens?

Answer 30

Endogenous: Cytotoxic T cells
Exogenous: Helper T cells

Question 31

What does “cross-presentation” refer to, with MHC presentation?

Answer 31

Exogenous antigens may be transferred to the ER and then be presented via the MHC I pathway, rather than the normal MHC II pathway

Question 32

When might cross-presentation be useful?

Answer 32

Some viruses and tumors do not ever go to the lymph nodes, and so dendritic cells may take up their peptides in the extracellular space as exogenous antigens, but then these peptides should be presented as endogenous antigens to cause the more effective cytotoxic T cell response

Question 33

What is “cross-dressing” in terms of MHC presentation?

Answer 33

Transfer of preformed peptide-MHC I complexes from the surface of infected cells to uninfected APCs, without the need of further antigen processing.

Question 34

What other molecule that’s similar to MHC I can also present antigens? What kind of antigens?

Answer 34

CD1 is structurally similar to MHC I (also has 3 alpha subunits and beta 2 microglobulin), and can present (amphipathic) lipid, glycolipid, or lipopeptide antigens.

CD1 groove is larger, deeper, and more hydrophobic, and so it allows hydrophobic things in its groove and shows the hydrophilic parts on the outside to T cell receptors

Question 35

How does the effect of superantigens differ from that of regular antigens?

What are 2 examples of superantigens?

Answer 35

Superantigens force an incorrect antigen presentation between TCR beta chain and MHC molecules. They cause non-specific T cell activation, polyclonal activation, with far too many cytokines being released -> systemic toxicity

Examples: SE (Staphyloccal enterotoxin), TSST-1 (toxic shock syndrome toxin-1 of staph aureus)

Question 36

What kind of diseases are associated with HLA allele problems?

Answer 36

Mainly autoimmune diseases, like HLA-B27 of ankylosing spondylitis
Also seen in Grave’s disease, gluten-sensitivity, myasthenia gravis, psoriasis, type I diabetes, and rheumatoid arthritis