MHC I and II molecules Flashcards
The MHC class I and class II molecules deliver peptides to the cell surface from two intracellular compartments
There are different mechanisms of delivering the presentation peptides through he MHC class I and II molecules:
- Peptides that bind to MHC I molecules:
come from the cytosolic pathogens, located in the cytosol, will be presented to the effector CD8 T cells and will result in cell death.
- Peptides that bind to MHC Class II molecules:
engages with the lymphoid cells. There are intravesicular pathogens (macrophages) that incorporate the pathogen in a vesicle, which present the pathogen to the effector CD4 T cells and will activate the killing of the microorganisms in the vesicle. And there are the extracellular pathogens and toxins, which also present the pathogen to the CD4 T cells, but they activate the B cells to secrete Ig to eliminate extracellular bacteria/toxins.
Exceptions after activation:
Some dendritic cells can form peptide:MHC class I complexes from peptides that were not generated within their own cytosol.
They can bind peptides from dying cells infected with cytosolic pathogens.
The cross presentation of exogenous antigens by MHC class I molecules, where the MHCII pathway happens to MHCI molecules, and vice versa.
Binding of peptides to the MHC Class I molecules
We need a mechanism to break peptides and also incorporate them in the ER, because MHC I are plasma membrane proteins so they need to be synthesised in the ER.
The protein is unstable without the peptide, and we need to transport the peptide in the MHC molecule. This can be done using ABC transporters, which have an ATP binding peptide.
The specific class of ABC transporters for MHC I molecules are the TAPs, which are transporters associated with antigen processing-1 and -2 (heterodimers), associated with the ER are:
- Inducible by interferons
- Viral infection the delivery of cytosolic peptides into the ER
- Specificity to small peptides with hydrophobic residues at the C-term.
The TAPs have a transmembrane domain and and an ATP binding cassette in the cytosol.
So it will bind the ATP, opens, binds the peptide, the peptide will move out of the transporter and is released in the lumen of the ER, and there it can be loaded in the MHC class I molecule.
Proteasome
Proteins in cells are continually being replaced by newly synthesized proteins and they are continually degraded.
They will have different half-lives:
- Eye lens crystallin: > 70 years
- Ornithine decarboxylase: 11 min
- Paratyroid hormone: 2 min
The proteasome binds huge proteins, unfolds them, and chops them into peptides.
The proteasome has a very symmetric structure and has different subunits for the binding of the protein, unfolding and the catalytic core is where it will chop the protein into peptides.
Inhibitors of the proteolytic activity of the proteasome inhibit antigen presentation by MHC class I molecules.
When some of the non-constituitive subunits are changed by the infection, we have the immunoproteasome, induced by interferons.
This is going to have different enzymatic specificity:
Increased cleavage of polypeptides after hydrophobic residues;
Decreased cleavage after acidic residues.
Molecules needed for loading the peptide into the ER
ERAAP (Endoplasmic reticulum aminopeptidase associated with antigen processing):
Amino termini of peptides can be produced by ERAAP trimming;
ERAAP upregulated by interferons.
The peptide produced by the immunoproteasome is not the final version, they are still going to be processed by the ERAAPS.
Calnexin: partly folded TCR, Igs, MHCII
ERp57: thiol oxidoreductase, rearranges disulfide bonds during peptide loading
PLC (minus TAP ) maintains the MHCI molecule in a state receptive to a peptide
ERp57:tapasin enable the exchange of low-affinity peptides for peptides of higher affinity (peptide editing)
Removal of the peptide from a purified MHC molecule requires denaturation
Many viruses produce immunoevasins that interfere with antigen presentation by MHC class I molecules
This process of binding peptides to the MHC molecules can be inhibited at the level of the transporters by blocking them, or act on the proteasome/chaperons.
Different viral cells affect the peptide loading process at different levels.
There are some viruses that block the entry of the peptide to the ER or cytosol. Another class of viruses can facilitate the retention of the MHC class I molecules in the ER, because they are competitors of the tapasin.
Other viruses can degrade the MHC class I molecules.
Binding of peptides to the MHC Class II molecules
Peptides presented by MHC class II molecules are generated in
acidified endocytic vesicles.
In the early endosomal compartment there will be a neutral pH, and then we have the acidification of the vesicle, and here the acidic proteases will be activated. The different proteases will generate the different types of peptides.
Chloroquine raise the endosomal pH and inhibits the presentation of intravesicular antigens.
IFNγ induces a lysosomal thiol reductase (GLIT) that predigests the proteins.
At neutral pH, empty MHC class II molecules are more stable than empty MHC class I molecules.
These peptides can be loaded into the vesicle that is coming from the ER that already made the class II molecules, and there is will have access to the peptide and will be loaded.
The intravarian chain directs newly synthesized MHC class II molecules to acidified intracellular vesicles.
Binding of MCH II to self peptides or antigens present in the ER is prevented by the binding of the intravarian chain Ii to the newly synthesized MHC class II molecule
They have a non-covalent binding.
In the absence of Ii many MHC class II molecules are retained in the ER as complexes with misfolded peptides.
MIIC
MHC class II compartment
(late endosomal pathway)
Immunoelectron-microscopy using antibodies tagged with gold particles.
MHC II that don’t bind peptide after dissociation from CLIP are unstable in the acidic pH after fusion with lysosomes and therefore they are rapidly degraded.
HLA-DM present at the MIIC binds and stabilizes empty MHC II and catalyzes the release of CLIP and the binding of other peptides.
It also has peptide editing activity
In the Golgi apparatus, we can see the two molecules: the intravariant chain and the MHCII molecules.
As it moves away from the Golgi apparatus, the intravariant chain will be lost, so this is where the loading of the new peptide will happen.
MHC molecules
- Polygenic: many genes
- Highly polymorphic: multiple alleles (population)
- Located on chromosome 6
- Contains more than 200 genes
- Spans 7 million base pairs
- Contains α chains of MHC I and α, β chains of MHC II
- β2–microglobulin encoded in chromosome 15
- Ii encoded in chromosome 5
MHC class I and II genes are called human leukocyte antigen (HLA).
DM - the molecule that will help the loading of the peptide into the class II molecules, so it is embedded in the region for class II.
DP, DQ (alpha beta) and DR (2 beta) - they can be carried by the human for the tissue type.
For Class I, there is HLA-A,B and C for the alpha chains.
So there are 6 different molecules for our tissue type.
The coordinated regulation of the adaptive immune response is likely facilitated by the linkage of the genes involved in these responses.
Interferons increase the transcription of MHC I genes, proteasome, tapasin, TAP .
Most individuals are heterozygous for both classes, meaning that we can carry different alleles for each gene.
Expression of MHC alleles is codominant;
MHC haplotype is the particular combination of MHC alleles in a single chromosome, so there are two haplotypes for each region, but it is still very diverse, and they will be different from each other.
Siblings have 25% probability of sharing both haplotypes, so therefore it is not easy to find a donor in the family, because it is not a match.
New MHC alleles arise by point mutations or gene conversion, so they are all together in the same genome and they share some similarity during meiosis there can be misalignments, and this is how gene conversion is generated.
Diversity of the MHC molecules
The MHC molecules have different forms, different versions of those, so different genes. And together there is polymorphism and polygeny.
The allelic variation for the different occurs at the level of the group.
Also, there is a MHC restriction, because the antigen bound to a T-cell receptor is a complex one, so there is a restriction even when the peptide could be able to bind to the cell receptor, the MHC molecule will always have the first interaction. So if they don’t interact then there is also no interaction to the T cell. Or the MHC molecule is not good, so the interaction will also not happen. So both the MHC molecules and the peptide are important, and it is good to have a diversity of the MHC molecules.
A variety of genes with specialized functions in immunity are also encoded in the MHC.
Not all MHC molecules will process peptides for the presentation to the T cells, they also have other functions in the immune system.
Some MHC class I-like genes map outside the MHC region.
Associates to β-microgobulin but behaves as MHC class II molecule.
It is targeted to vesicles where it binds its ligand.
Binds glycolipids, phospholipids and lipopeptide antigens due to a hydrophobic channel in its groove.
Super-antigens
A super-antigen is a molecule that is able to interact with a T cell receptor and the MHC molecule and bring them together. So it can activate a lot of T cells.
- Recognized by T cells without being processed into peptides that are captured by MHC molecules.
- Intact proteins
- Bind to a MHC molecule that has already bound peptide
- They are able to bind the Vβ region of many TCRs (Mainly CDR2, CDR1)
- Can stimulate from 2-20% of all T cells
- Stimulate very large numbers T cells
- Cause massive production of cytokines by
- CD4 T cells:
- Lead to systemic toxicity and suppression of the adaptive immune response.
SE staphylococcal enterotoxins
Cause food poisoning
TSST-1 toxin shock syndrome toxin-1
From staphylococcus aureus
> 20kDa
TSS caused by localized infection with toxin-producing stains of the bacterium
