Costimulation – Lymphocyte Activation

00:01 In order to activate lymphocytes, stimulation through the antigen receptor alone is not sufficient.

00:10 You need what is referred to as co-stimulation.

00:16 So here we have a T-cell, that’s a naïve T-cell, it hasn’t encountered antigen before.

00:22 Its T-cell receptor is recognizing peptide MHC on the surface of an antigen presenting cell, like a dendritic cell. So this APC (antigen presenting cell) is showing peptide together with MHC to the T-cell receptor on the naïve T-cell.

00:38 But actually nothing’s happening, because that’s the only signal that the T-cell is getting.

00:44 And the result, if there is stimulation only through the antigen receptor, will be that there is actually functional inactivation of the T-cell; a process that is referred to as anergy.

00:56 So there’s no response and we have a form of immunological tolerance.

01:02 And this process of inactivating T-cells is very useful in preventing unwanted reactivity against self antigens.

01:13 However, in the context of infection, dendritic cells become activated by the Pathogen-Associated Molecular Patterns present on microbes.

01:24 And part of that activation of the dendritic cell, causes them to increase the expression of co-stimulatory molecules like the B7 molecules and also to release co-stimulatory cytokines such as interleukin-12.

01:40 So in the context of infection, dendritic cells up-regulate the co-stimulatory molecules and cytokines that are required for T-cell activation.

01:51 This will cause T-cells to themselves produce cytokines such as interleukin-2, and this will feed back onto the interleukin-2 receptor which is also expressed on these T-cells.

02:03 And you’ll get extensive proliferation following activation of these T-cells, the development of effector T-cells, T-cell survival, proliferation and differentiation.

02:14 The CD80 and CD86 B7 molecules are not the only molecules that are involved in co-stimulation.

02:21 So here we have an example of a dendritic cell that is expressing the molecule CD40 on its cell surface.

02:31 When the T-cell is stimulated by the dendritic cell, one of the things that can happen is that CD40 ligand becomes expressed on the T-cell.

02:47 And the CD40 ligand binds to the CD40 on the dendritic cell.

02:53 And this can lead the dendritic cell to express higher levels of B7.

02:59 So there’s a feedback loop whereby interaction of CD40 ligand on the T-cell with CD40 on the dendritic cell, causes the dendritic cell to increase its expression of the B7 molecule - CD80 and CD86; and also to release cytokines.

03:17 So the activated dendritic cells stimulate T-cell proliferation and differentiation.

03:23 They have on their cell surface all the molecules now required to do that.

03:27 They have MHC and peptide that can stimulate the T-cell receptor.

03:32 They have CD40 that stimulates through CD40 ligand.

03:36 And crucially, they have those all important B7 molecules that can co-stimulate via the CD28 molecule on the surface of the T-lymphocyte.

03:47 And also they’re producing cytokines that further aid in the activation.

03:51 So you have enhanced T-cell proliferation and differentiation resulting from these co-stimulatory signals.