00:01
Let’s now look in a little bit more detail about
the actual development process in the thymus.
00:07
We’ve heard that the T-cells migrate
through the cortex and into the medulla.
00:11
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.
00:28
We therefore refer to them as being CD8
negative (CD8-), CD4 negative (CD4-).
00:34
And immunologists use a bit of jargon
that’s called ‘double negative T-cell’.
00:38
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.
01:11
And the first step in thymic education which takes place in the
cortex is interactions of the T-cells
with thymic epithelial cells.
01:20
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.
01:34
It’s no good if the T-cell receptor can’t recognize MHC
because we’re talking about alpha beta (αβ) T-cells here.
01:40
They need to recognize
peptide presented by MHC.
01:43
They need to recognize peptide presented by our own
variants of the MHC, not somebody else’s variant.
01:49
So the first stage in thymic education
is called positive selection.
01:55
And T-cells are selected positively if they are able to
recognize peptides presented by our own MHC molecules.
02:04
If they fail to do so, they
die by apoptotic cell death.
02:10
So, positive selection rescues from
apoptosis, cells that recognize ‘self’ MHC.
02:21
This is followed by negative selection,
where there is induction of apoptosis
if the T-cells recognize autoantigens,
in other words, self antigens.
02:33
And this process constitutes what we
refer to as central tolerance.
02:37
We say that immune cells, and we’re
referring here specifically to
lymphocytes; that the lymphocytes
become tolerant to self antigens.
02:46
They don’t react to self antigens.
02:48
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.
03:06
If the T cell had produced a T cell receptor
capable of interacting with MHC class 1,
then CD4 is switch off.
03:16
Whereas, if the T cell receptor is
capable of interacting with MHC class 2,
then CD8 is switched off.
03:23
So these T cells become what
we call single positive T cells,
in other words either
CD4 positive or CD8 positive.
03:33
The T cells then leave the thymus and
go to the secondary lymphoid tissues.
03:40
The diversity of the T cell receptor
is generated by mechanisms
that are essentially identical to
those that generate the B cell receptor.
03:51
In other words, they are a set of
T cell receptor genes that recombine.
03:58
Here we can see the numbers of
gene segments that were involved.
04:07
For the T cell receptor alpha chain there
are 75 variable gene segments approximately,
no diversity segments, and around
about 60 joining or J gene segments.
04:21
Whereas, for the beta chain, there
are approximately 50 V gene segments,
two diversity gene segments,
and 13 J gene segments.
04:33
Regarding the gamma delta T cell receptor,
there are around about 15 V segments, no Ds, 5 Js.
04:45
And for the delta chain, 8 Vs, 3 Ds and 3 Js.