Chapter 7: Major Histocompatibility Complex

Question 1

What are MHC proteins?

Answer 1

Membrane-bound surface proteins found on antigen presenting cells that are important for tissue recognition. In humans they are referred to as HLA (human leukocyte antigens)

Question 2

What are the three classes of MHC genes?

Answer 2

Class 1 and 2 encode glycoproteins.
Class 1 are expressed on all nucleated cells (not erythrocytes)
Class 2 are expressed on antigen presenting cells (macrophages, B-cells, dendritic cells) and occasionally thymic epithelial cells, endothelial cells etc. if induced (by interferon-y)
Class 3 encodes products involved in complement and inflammation, but not covered in this unit.

Question 3

Define haplotype

Answer 3

Set of alleles for a given gene. In MHC molecules, each haplotype is given a number (HLA A2 B5, meaning you have an A and a B allele for that gene). Most of the population is heterozygous which generates a lot of immunologic diversity (but hard for transplants). These genes are codominant (both are expressed)

Question 4

What does it mean to be highly polymorphic?

Answer 4

Meaning there are many many different allelic variants

Question 5

What is the basic structure of MHC Class 1 molecules?

Answer 5

Two non-symmetrical/ uneven chains: a trans-membrane a-chain (a1 and a2 are variable and form a binding cleft, a3 is not variable and contains binding site for CD8+ coreceptor
A B-micro-globulin Which just “hovers” next to the a3 domain near the membrane
—> Binds 8-10 amino acid peptide fragments from an antigen
—> found on all nucleated cells

Question 6

MHC class 2 structure

Answer 6

Two largely symmetrical chains: a1 and B1 are variable/ polymorphic and contain the binding groove. A2 and b2 are nonpolymorphic and contain the binding site for CD4+ T-cells
—>binds peptides between 13-18 amino acids long
—> Found on antigen-presenting cells (occasionally thymus)

Question 7

How are the genes for the MHC molecule expressed?

Answer 7

Alleles are codominant and expressed simultaneously

Question 8

What type of molecules (where they originate) do each class of MHC present

Answer 8

• Class 1 presents intracellular (endogenous) antigen peptides, as well as self-proteins. Activates cytotoxic T-cells
• Class 2 presents extracellular (exogenous) antigen peptides display to and activate helper T-cells

Question 9

What part of MHC binds CD4 or CD8? Where are these co-receptors found?

Answer 9

• On MHC1, a3 domain binds CD8+ cytotoxic T-cell coreceptor

- On MHC2 a2 AND B2 contain site to bind CD4+ helper T-cell coreceptor

Question 10

Why is it important to be able to express many different MHC proteins?

Answer 10

It gives the best chance for an organism to have SOME ability of presenting alL the possible antigen peptides it encounters. Also allows presentation of both extracellular (class 2) and intracellular (class 1) antigens

Question 11

What type of cells present class 1?

Answer 11

All nucleated cells

Question 12

What types of cells express MHC class 2?

Answer 12

Antigen presenting cells (macrophages, B-cells and dendritic cells)

Question 13

What is required for a MHC molecule to become stable (resistant to proteolysis)?

Answer 13

Stable expression requires peptide cargo (peptide antigen is linked to MHC during the MHC assembly inside the cell). If not linked, will be degraded.

Question 14

What are the types of antigen presenting cells? What is their “professional” status and what types of cells do they present to?

Answer 14

• Dendritic cells (professional APC) present to naïve T-cells and cause them to undergo clonal expansion/ differentiation
• Macrophages, present to differentiated effector T-cells
• B-cells present to differentiated helper T-cells
• All nucleated cells can present from intracellular microbes or cancer to cytotoxic T-cells that are already differentiated

Question 15

What is the function of antigen presenting cells?

Answer 15

• capture antigens
• take them to the correct site (secondary lymphoid organs)
• display antigens so they can be recognized by lymphocytes
• provide second signals for T-cell activation (signal 2= expression of costimulators and secretion of cytokines by APC)

Question 16

Steps for MHC Class 1 antigen processing and presentation

Answer 16

• Endogenous/ Cytosolic pathway
  1. Endogenous (from cytosol) antigen tagged by ubiquitin degraded by proteosome (or immunoproteosome if not tagged)
  2. Peptide is transported to rough ER via TAP (transporter associated with antigen processing) using ATP
  3. The a chain binds to calnexin chaperone, induces conf. Change and allows B2 to bind. Calnexin can then dissociate.
  4. Tapasin chaperone protein binds, associating MHC-1 w/ TAP-antigen fragment complex, allowing processed antigen to be loaded
  5. MHC-1+peptide transported from RER to golgi complex to plasma membrane on cell surface

Question 17

Steps for MHC class 2 antigen processing and presentation

Answer 17

Endocytic (Exogenous) pathway

1. Exogenous antigen is endocytosed (phagocytized), and degraded in phagolysosome
2. At the same time, MHC-2 is synthesized in ER. Invariant protein binds and blocks peptide binding groove of MHC where antigen would normally bind
3. Invariant chain signals the move from RER through golgi to meet up and merge with lysosome w/ the antigen peptide fragments
4. In the lysosome, invariant protein is degraded by low pH, leaving only CLIP in cleft
5. HLA-DM protein exchanges antigen for CLIP in MHC binding site
6. The fully formed MHC-2 w/ associated peptide is then embedded in cell surface membrane via exocytosis

Question 18

What is cross presentation?

Answer 18

The ability of certain antigen-presenting cells to take up, process and present extracellular antigens using MHC CLASS 2 molecules to CD8+ T-cells. This stimulates naïve cytotoxic T-cells into activated T-cells

Question 19

What are ways viruses can evade antigen presentation?

Answer 19

1. They can escape from the proteasomal cleavage (block lysosome fusion, survive phagocytosis etc.)
2. It can block the function of the TAP transporter so the antigen never enters the ER
3. It can inhibit the Tapasin chaperone protein so assembly doesn’t happen and MHC is degraded
4. Can send MHC-1 to lysosome to be degraded, can keep in the ER so never make it to cell surface, or can down-regulate expression of MHC-1 generally.