So these molecules vary hugely
from one individual to another.
We call them polymorphic.
In fact the MHC genes are the most polymorphic
genes in the whole of the human genome.
So why is that?
Why do they vary so much from
one individual to another?
Well the most likely reason is that during evolution, they
have diversified so that at least at a population level, there
is a huge diversity of MHC that is able to present to T-cells
almost any pathogen that might arise during evolution.
So, evolution is worried more about the
population level than the individual.
So it may be that your MHC molecules may not present
peptides from a certain virus, but other people’s will.
At the tip of the MHC molecule, there is a
peptide binding groove that binds the peptide.
And as you can see, in the peptide binding groove there
is a beta (β)-sheet floor and there are alpha (α)-helices.
And the β-sheet floor and the two
α-helices are the bits that vary from
one individual to another, and
between the different MHC molecules.
And the same is true for MHC Class II; β-sheet floor and the
α-helices are the polymorphic regions that bind the peptide.
However there are also non-polymorphic regions,
not associated with the peptide binding groove.
And they are important in the
binding of other molecules to MHC.
So for example, the molecule CD8 binds
to non-polymorphic regions of MHC Class I
whereas the molecule CD4 binds to
non-polymorphic regions of MHC Class II.
The fact that the T-cell receptor has
to recognize a combination of peptide
MHC which we can abbreviate to a lowercase
pMHC, ensures cell-cell contact.
So here we can see an MHC Class
I molecule presenting peptides.
And this is going to present those
peptides to a CD8+ cytotoxic T-cell.
So we have a cell infected with a virus for
example, that viral… virus will be broken down
and its proteins will be chopped up into
peptides and put together with the MHC molecule.
And the T-cell receptor will recognize a
combination of the peptide plus MHC Class I.
And because this cell is a CD8+ cytotoxic T-cell,
it will recognize peptides presented by MHC Class I.
And that’s an absolute correlation.
If a T-cell is a CD8+ T-cell, it recognizes
peptides presented by MHC Class I, if it’s
a CD4+ T-cell, it recognizes peptides
presented by MHC Class II without exception.
And following that interaction between the T-cell receptor
and the peptide MHC Class I, and the CD8 binding to
non-polymorphic regions, a peptide, a pMHC Class I,
there’ll be a signal sent in to the nucleus of the T-cell.
This will result in activation of the cytotoxic
T-cell, and this will kill the infected
cell using either the fas-fas ligand pathway
of inducing apoptotic cell death or the
perforin-granzyme pathway of causing apoptotic
cell death in the infected cell; either
way that cell will be destroyed and will
no longer serve as a home for the virus.
In terms of recognition of peptide MHC Class II as we’ve
already heard, unlike MHC Class I which is found on all
nucleated cells, and it needs to be because any nucleated
cell can become infected with some virus or another.
So that needs to be a
So all nucleated cells
need to have MHC Class I.
But the job of activating helper T-cells
and regulatory T-cells can be given over to
a specialized group of cells, and this is
the professional antigen presenting cell.
And they are able to show peptides
to the T-cell receptor on CD4+ cells.
And the vast majority of CD4+ cells are
either helper T-cells or regulatory T-cells.
And again, subsequent to binding of the T-cell receptor
peptide MHC, a signal is sent into the T-cell to activate it.
And this will result in the release of cytokines from
helper T-cells and also regulatory T-cells can secrete
cytokines and they can also suppress immune responses in
a cell-cell contact dependant way; which again is a good
reason why there needs to be this intimate interaction
enforcing the cell-cell contact by the T-cell receptor on
the surface of the T-cell interacting with peptide MHC on
the surface of the professional antigen presenting cell.
And these cytokines that are released will act locally within
the environment in which the T-cell is being stimulated.