L3 - Genetics of antigen recognition receptors (TCR & MHC) Flashcards
How are TCR polypeptides encoded?
By rearranging genes
Variable regions encoded by V, (D) & J segments
Gene segments rearrange during T cell development in the thymus (not bone marrow)
Gene segment rearrangement during T cell development in the thymus
Once they get into the thymus they turn on RAG1 & RAG2 genes & start doing this process in the thymus
What happens if you have mutations in RAG genes?
Patients with mutations in RAG1&2 will have no T cells as well as no B cells – so will have no acquired immune system – SCID
Generation of diversity in TCR
Similar mechanisms to Ig
Multiple V, (D) & J gene segments
Combinational diversity
Junctional diversity
However, no somatic hypermutation occurs in TCR genes
TCR generation
The different components of the variable regions are spaced out in the genome
The genes get closer together by breaking & repairing
There are no D regions in the alpha – only V & J
Alpha chain can then bind to the beta chain
Beta chain has a D region
End up with a receptor that has a high variability in the antigen recognition site
Recognises peptides displayed my MHC molecules
What other chains can T cells express other than alpha & beta?
Can also be gamma or delta – from the same chromosomes
They either express one or the other sets
MHC diversity
No gene rearrangement occurs
Genes located within MHC (HLA in humans on chromosome 6)
Don’t have allelic exclusion on MHC molecules – MHC molecules can be made from each chromosome & can be co-dominant (heterozygous)
MHC expression on class I & II
Class I expressed by all nucleated cells
Class II expressed on particular cell types – APCs (B cells, macrophages & dendritic cells)
– Up-regulated & induced by interferon
Gene structure of the human MHC
Class I region – where class I genes live
Class II region – where class II genes live – Are dimers – HLA:DP-DQ-DR: have an alpha & beta chain gene for each
Class III region – other genes that are related to the immune system but not related to MHC
Dimers that make up class II MHC
DP has alpha & beta gene
DQ has alpha & beta gene
DR has an alpha & 2 beta genes
Whats the most MHC an individual can have?
A single individual will have up to 12 different MHC molecules (if they’re heterozygous for all 6 MHC loci)
What are polymorphic genes?
Can be a single base pair different
MHC molecules are the most polymorphic genes known
Co-dominant expression of MHC molecules
3 MHC class I molecules (HLA-A, HLA-B and HLA-C)
If heterozygous at each loci, one person can express six different class I molecules
Similarly, for class II (HLA-DP, HLA-DQ and HLA-DR)
Where are polymorphic residues within MHCs located?
Polymorphisms are within the peptide binding groove – affects the ability to bind peptides
Reason for such high levels of MHC polymorphism
Allows the binding if a vast range of peptides that can be presented to T cells – provides a clear evolutionary advantage to the population
Disadvantages of high levels of MHC polymorphism
Increases risk of many immune-mediated diseases
Makes selection of suitable donor organs for transplantation very complex & inefficient
How do peptides end up on the surface of cells bound to MHC molecules?
ANTIGEN PROCESSING & PRESENTATION
Antigen processing and presentation in MHC
MHC molecules present the peptides
Before they do that the cells that express the MHC have to process the antigen to allow the peptides to fit in the groove of the MHC molecules
Endogenous antigens
If a cell makes a protein that’s going to be put on a MHC it goes onto a MHC I molecule
If a cell is infected with a virus, the cell starts to make the viral proteins – proteins will be loaded onto the class I as its made within the cell
When the cells not infected, the proteins are from its own proteins – class I
Exogenous antigens
APCs take things up from the outside of cells – generate peptides from wheat they’ve taken up
Load peptides onto MHC II molecules
APCs capture antigens & express them
Presentation of Ag by MHC I molecules
- Ag (eg. viral protein) synthesised in cytoplasm
- Protein cleaved to peptides by proteasome
- Peptides transported to endoplasmic reticulum by TAP transporter
- Peptides bind to MHC I molecules
- MHC-I/peptide complex then transported to cell surface
Where are class I MHC when theres no peptides?
Stays in the ER
Where are class I MHC where there are peptides present?
Peptides go through the TAP transporter & binds to class I
Once it binds it changes its shape & releases these chaperones & class I can leave via a vesicle to go to the cell surface
Presentation of Ag by MHC II molecules
- Ag endocytosed into intracellular vesicles inside the cell
- Protein cleaved to peptides by acid proteases in vesicles in the endocytic pathway
- Vesicles fuse with vesicles containing MHC II molecules
- Peptides bind MHC II molecules
- MHC-II/peptide complex then transported inside vesicle to cell surface in the endocytic pathway
Why doesn’t class II bind peptides in the ER??
Has an invariant chain bound in its binding cleft which stops peptides getting into the cleft while still in the ER - stops class II going to the cell surface
Invariant chain has a sequence in its cytoplasmic tail which takes it into the endocytic pathway where enzymes can chop up the invariant chain – leaves the CLIP peptide associated with the binding groove
Peptides from antigen displace CLIP when they bind
HLA-DM, a class II-like molecule, is required for loading of peptides into the groove
Function of the invariant chain?
Invariant chain protects the class II MHC from picking up peptides that are expressed by MHC I
What molecule is required for loading of peptides into groove of class II MHC?
HLA-DM A class II-like molecule
What happens with MHC in normal healthy uninfected cells?
MHC I & II molecules will bind & present peptides from self-proteins
What are the accessory molecules in antigen processing & presentation?
DM (alpha&beta) – takes invariant chain off class II & puts peptides on
TAP – delivers peptides to the ER for class I MHC
LMP – encodes subunits for the proteasome
Where are the accessory molecules encoded?
Encoded within the MHC
Kept evolutionary together – all involved in antigen processing
APCs
As all nucleated cells express MHC I, any cell infected with a virus can present viral peptides on the MHC I & be recognised & killed by cytotoxic CD8+ T cells
Only APCs express MHC II which take up & present extracellular Ag to activate helper CD4+ T cells
