Cell-mediated Immunity: Gamma-Delta T-Cells, T-Cell Receptor, and Alpha-Beta T-Cells

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.