Antigen processing and presentation

Question 1

What are the 2 pathways that MHC molecules present peptide fragments of protein antigens to T-cells via?

Answer 1

• Endogenous (Class I)
• Exogenous (Class II)

Question 2

What are MHC molecules composed of?

Answer 2

4 immunoglobulin superfamily domains

Question 3

What does MHC Class I have (composition)?

Answer 3

An α-chain with 3 domains non-covalently associated with β2-microglobulin

Question 4

What do MHC class II have? (composition)

Answer 4

An α and β chain

Question 5

What are the functions of the α and β chain in MHC class II

Answer 5

The α-helices and β-pleated sheet form the sides & floor of the peptide binding groove in MHC molecules.

Question 6

How are peptides held in place with MHC molecules via?

Answer 6

With ionic, hydrophobic and hydrogen-bond interactions/

Question 7

Cytosolic proteins and extracellular proteins pathway diagram

Answer 7

Question 8

Endogenous vs Exogenous pathway comparison chart

Answer 8

Question 9

Endogenous pathway

Answer 9

1. It exploits normal “housekeeping” machinery by ubiquitination of viral/bacterial cytosolic proteins where they are transported to proteasomes in the cytosol
   2. The immunoproteosome contains LMP-2, LMP-7 and LMP-10 subunits & preferentially generates peptides with basic/hydrophobic C-termini that bind to MHC Class I
   3. LMP-2, LMP-7 &LMP-10 are induced by IFN-γ
   4. LMP-2 & LMP-7 genes are polymorphic & encoded in the Class II region of MHC
2. These are cleaved into peptide fragments before being transported into the RER
   
   1. Peptides are generated in the cytosol but MHC Class is synthesized in RER
3. They are transported into the RER via TAP-1 & TAP-2 (transporters for Ag processing) that convey the peptide to the RER. This requires ATP
   
   1. TAP has a transmembrane domain & an ATP-binding cassette (ABC) domain in cytosol
   2. Transports 8-10 a.a. peptides with hydrophobic C-termini (i.e. optimised for MHC Class I binding)
   3. TAP-1 & TAP-2 genes are polymorphic & are encoded in the MHC
4. The MHC Class I α-chain & β2-microglobulin are produced in RER. A series of chaperones orchestrate folding & loading of MHC Class I molecules
   
   1. Calnexin associated with the α-chain and promotes correct folding.
      
      1. Calnexin is released when the α-chain contacts β2-microglobulin
   2. Calreticulin binds to the MHC Class I α/β2-m dimer & brings it to a TAP-associated protein, Tapasin
      
      1. Peptides entering RER lumen from TAP are captured & loaded onto MHC I
5. Only folded & loaded MHC I α/β2-m/peptide complexes dissociate from Calreticulin & migrate to the cell-surface via the golgi apparatus

Disorders

Patients with Type I Bare Lymphocyte syndrome have defective TAP-1/TAP-2 & express no MHC Class I on the cell surface (suffer from chronic lung infections & skin autoimmunity).