00:01
Let’s just spend a couple of moments to look at gamma-delta
(γδ) T-cells, and exactly what they do and what they are.
00:09
They appear to have a distinct role that is
complementary to that of the alpha-beta (αβ) T-cells.
00:16
They comprise less than
five percent of the T-cells.
00:19
So they’re very much a
minority population of T-cells.
00:22
And they’re present mostly in the gut mucosa,
in the skin, in the lungs and in the uterus.
00:29
And they can directly recognize microbial pathogens,
and also damaged or stressed host cells.
00:35
In other words, our own cells that are damaged
due to infection or other types of pathology.
00:42
To give you just a couple of examples of the
recognition that can occur by γδ T-cells.
00:48
You can have direct recognition of
phosphoantigens from Mycobacterium tuberculosis,
from Plasmodium malariae without any
requirement for antigen processing whatsoever.
01:03
And there can be direct recognition of the
MHC-like non-peptide-binding molecules,
MICA and MICB, or of CD1 irrespective of
any lipoprotein or glycolipid antigen.
01:17
So they can recognize structures that are
coming from foreign pathogens, but they can also
recognize our own molecules that are upregulated
in response to stress or other events.
01:29
Here’s the structure of the T-cell
receptor on the surface of a T-lymphocyte.
01:34
It’s a heterodimer,
consists of two chains.
01:38
And here we can see the
αβ T-cell receptor.
01:42
The γδ T-cell receptor
looks almost identical.
01:49
In both cases, the two chains of the T-cell
receptor are linked together by a disulfide bond.
01:56
There are transmembrane segments associated
with both chains of the T-cell receptor.
02:02
Each chain is folded into two domains; a Variable
domain which is stabilized by an intra-chain
disulfide bond, and a Constant domain also
stabilized by an intra-chain disulfide bond.
02:17
Looking at exactly how the T-cell receptor
interacts with peptide MHC; at the
top of this diagram, we can see the two
Variable domains of the T-cell receptor.
02:31
Underneath is the MHC Class I α-chain.
02:37
This is associated
with β2-microglobulin.
02:42
And then sitting between the α-helices of the
MHC Class I α-chain is the antigenic peptide.
02:51
And this is making contact not only with the
MHC but also with the hypervariable or CDR
regions of both the α-chain and the β-chain
of the T-cell receptor Variable regions.
03:06
αβ T-cells, are not all the same.
There’s a variety of
different types of αβ T-cells.
So let us look at the different types.
03:16
Well, there are ones that have CD4 on their cell surface
and there are others that have CD8 on their cell surface.
03:23
So that’s one distinction.
03:25
Within the CD4+ αβ T-cells, there are
a number of subpopulations - Th1,
Th2, Th17, T-follicular helper and
T-regulatory cells amongst others.
03:41
These are the most important, or at least the
best characterized at this point in time.
03:49
They can be distinguished by a
number of different features.
03:53
So if we look at the transcription factors that
are expressed in the nucleus of these different
types of T-cell, we see that Th1 cells express
the transcription factors T-bet and STAT4.
04:09
They produce a variety of different cytokines - gamma
interferon, interleukin-2, tumor necrosis factor beta.
04:18
These are typical cytokines
that are produced by Th1 cells.
04:22
And in fact, the first distinction
of these different types of helper
T-cells was based upon the particular
cytokines that they produced.
04:31
The primary function of Th1 cells is to help
cytotoxic T-lymphocytes and to help macrophages.
04:38
Although, they can also help
some B-cells to produce antibody.
04:42
Importantly, they can inhibit
the activity of Th2 cells.
04:48
Turning now to Th2 cells, they express the
transcription factors GATA3 and STAT6 in their nucleus.
04:55
They produce the cytokines
interleukin-4, IL-5, IL-6 and IL-13.
05:01
And their primary function
is to help B-cells.
05:05
Importantly, just like Th1 cells can inhibit
Th2 cells, so Th2 cells can inhibit Th1 cells.
05:13
So these two populations, Th1 and Th2, at least to some
extent are mutually antagonistic towards each other.
05:22
Th17 cells express the transcription
factor RORγt in the nucleus.
05:28
And as their name suggests, they produce interleukin-17,
amongst other cytokines such as interleukin-22.
05:36
And these cells are really
specialized to promote inflammation.
05:41
T-follicular helper cells are cells that
are found in the germinal centers of
secondary lymphoid tissues where they
assist in the activation of B-lymphocytes.
05:53
They express the
transcription factor Bcl-6.
05:56
And they produce cytokines such
as interleukin-21 and ICOS.
06:02
And as I’ve already mentioned, their
function is to help germinal center B-cells.
06:05
So those four cell types all enhance immune
responses, they help immune responses.
06:12
In contrast, T-regulatory cells
suppress immune responses.
06:17
And they express the transcription
factor Foxp3 in their nucleus,
very characteristic transcription factor of regulatory T-cells.
06:26
The cytokines they produce tend to be cytokines
that overall have immunosuppressive activity.
06:34
Cytokines such as transforming growth factor
beta, interleukin-10 and interleukin-35.
06:40
And again as I’ve already mentioned, the primary
function of T-regs is to suppress immune responses.
06:47
So those are different types of CD4+ αβ T-cells.
06:51
What about the CD8s?
Well, these are generally
cytotoxic T-lymphocytes.
06:57
And they express in their nucleus,
the transcription factor RUNX3.
07:03
They function by producing molecules
such as perforin, granzymes,
Fas ligand, but they can also produce a variety of cytokines.
07:14
And their role is to
kill infected cells.
07:18
Let's take
a quick look at MAIT cells
or mucosal associated
invariant T cells.
07:23
They can represent up to 10%
of circulating T cells,
but are also found
in the liver.
07:28
Mucosal linings
and other tissues.
07:31
They have an invariant
TCR alpha chain
that is linked
with the restricted
repertoire of TCR
beta chains.
07:37
Most of these cells
fall into the CD8 category
and recognize antigens
presented by non polymorphic
MHC one like molecules MR1.
07:46
They function rapidly
similar to our innate
anti-microbial response,
and this is mediated
through the release
of inflammatory
cytokines listed here.