Lecture 5 - MHC class I presenting

Question 1

Difference between MHC I and MHC II cells

Answer 1

MHC-I restricted effector cytotoxic CD8+ T cells target cells infected with viruses and other intracellular pathogens, leading to lysis of infected cell

MHC-II restricted effector CD4+ T cells recognise antigen displayed by professional antigen presenting cells and then “help” other cells of the immune system

(2 x 4 = 1 x 8)

Question 2

Are maternal or paternal MHC genes expressed?

Answer 2

MHC genes are codominantly expressed

Question 3

What are MHC genes called in humans?

Answer 3

Human leukocyte antigen (HLA) genes

Question 4

MHC: how many types are there, are there variations among the population, and is this beneficial?

Answer 4

Polygenic - contains several different MHC class I and class II genes

Highly polymorphic - there are multiple alleles of each gene within the population

Beneficial - it is unlikely that any one pathogen will be able to avoid the immune response in an entire population

Question 5

MHC I structure

Answer 5

MHC-I is a heterodimeric glycoprotein composed of transmembrane polymorphic alpha chain (43kDa) + invariant β2-microglobulin chain (12kDa)

The two chains are non-covalently linked

The alpha chain has 3 distinct domains and the closed peptide-binding groove is formed between the α1 and α2 domains

α1 and α2 domains are polymorphic, determining the type and sequence of peptide that can bind
Gives specificity

Question 6

Peptide Binding in MHC-I

Answer 6

Rewatch

Question 7

Anchor residues

Answer 7

Anchor residues (ARs) within the peptide determine the binding to specific MHC-I variants.
creates diversity in the peptides that can be bound.

Anchor residues do not have to be identical A.A, but they must have comparable properties to bind to a given MHC variant
-ie hydrophobic, or aromatic

Any given MHC-I molecule can theoretically bind any number of peptides, as long as they are comparable at the anchor residues
Each peptide-MHCI complex is recognised by a distinct TCR on T cells = Specificity

Question 8

MHC class I location

Answer 8

Antigen fragments that bind MHC class I are typically viral derived, made in the cytosol. These antigens do not fit directly into the peptide binding groove-too long, not the correct conformation, not the correct charge etc…

The MHC class I molecule is assembled in the lumen of the endoplasmic reticulum, the peptide-binding site of MHC I is never exposed to the cytosol.

Questions
How does MHC class I bind the cytosolic peptides?
MHC class I binds particular types of peptides with specific anchor and amino and carboxy termini residues. How are these particular peptides generated?

Question 9

Proteasome: what is it, what is its structure, and what does it do?

Answer 9

Large, multicatalytic protease complex
Cylindrical complex of 28 subunits; 4 stacked rings, each of 7 subunits
Hollow core lined by active sites of proteolytic subunits
Proteins enter the core and are broken down into short peptides and released for transport by TAP complex
Proteasome degrades ubiquitin-labelled proteins
Tagging protein with Ubiquitin increases MHC presentation of the protein’s peptides