Let’s now look in a little bit more detail about
the actual development process in the thymus.
We’ve heard that the T-cells migrate
through the cortex and into the medulla.
So exactly what’s going on during
those migration processes?
Well when the T-cells first enter
the thymus, having come from the
bone marrow, they lack expression
of two molecules - CD4 and CD8.
We therefore refer to them as being CD8
negative (CD8-), CD4 negative (CD4-).
And immunologists use a bit of jargon
that’s called ‘double negative T-cell’.
So if you hear an immunologist
talk about double negative T-cells,
you wouldn’t know what on earth they were talking about.
But what they’re actually referring to is cells that
are CD4-, CD8-, lacking both of those molecules.
Shortly after arrival in the thymus, the genes for both
of those molecules are switched on and these T-cells
become CD4 positive (CD4+), CD8 positive (CD8+); in
other words in the jargon, ‘double positive T-cells’.
These are now ready to
undergo thymic education.
And the first step in thymic education which takes place in the
cortex is interactions of the T-cells
with thymic epithelial cells.
And the purpose of this interaction is to
ensure that the T-cell receptor that has
been generated by random recombination is
able to recognize our own MHC variants.
It’s no good if the T-cell receptor can’t recognize MHC
because we’re talking about alpha beta (αβ) T-cells here.
They need to recognize
peptide presented by MHC.
They need to recognize peptide presented by our own
variants of the MHC, not somebody else’s variant.
So the first stage in thymic education
is called positive selection.
And T-cells are selected positively if they are able to
recognize peptides presented by our own MHC molecules.
If they fail to do so, they
die by apoptotic cell death.
So, positive selection rescues from
apoptosis, cells that recognize ‘self’ MHC.
This is followed by negative selection,
where there is induction of apoptosis
if the T-cells recognize autoantigens,
in other words, self antigens.
And this process constitutes what we
refer to as central tolerance.
We say that immune cells, and we’re
referring here specifically to
lymphocytes; that the lymphocytes
become tolerant to self antigens.
They don’t react to self antigens.
And this negative selection in the
thymic medulla, where the T-cells
interact with dendritic cells and macrophages that are showing
self antigens to the T-cells, if
there is recognition of these self
antigens, apoptosis is induced and
those cells are got rid of.
Following these positive and
negative selection events, the cells
switch off expression of either the CD4 or the CD8 gene.
If the T-cell had produced a T-cell receptor capable
of interacting with MHC Class I, then CD4 is switched
off; whereas if the T-cell receptor is capable of
interacting with MHC Class II, then CD8 is switched off.
So these T-cells now become what we call ‘single
positive’ T-cells, in other words, either CD4+ or CD8+.
The T-cells then leave the thymus and
go to the secondary lymphoid tissues.
The diversity of the T-cell receptor is generated by
mechanisms that are essentially identical to those
that generate the B-cell receptor, in other words, there
are a set of T-cell receptor genes that recombine.
Here we can see the numbers of
gene segments that are involved.
For the T-cell receptor α chain,
there are 75 Variable gene segments
approximately, no Diversity segments,
and around about 60 Joining or
J gene segments; whereas for the β
chain, there are approximately 50
V gene segments, two Diversity gene
segments and 13 J gene segments.
Regarding the gamma (γ) and delta (δ)
T-cell receptor, there are around about 15
V segments, no Ds, five Js; and for the δ
chain, eight Vs, three Ds and three Js.