T cell triggering

When reading immunology textbooks I had the feeling that one important point was not explained. The T cell receptor is almost entirely outside the cell and so when it encounters its antigen it cannot transmit this information into the cytosol the way a transmembrane receptor does. But since the activation of the cell involves the phosphorylation of the cytoplasmic tails of proteins associated to the receptor (CD3 and the \zeta-chains) the information must get through somehow. So how does this work? This process, which precedes the events relevant to the models for T cell activation I discussed here, is referred to as T cell triggering. I had an idea about how this process could work. If the T cell receptor and the coreceptor CD8 both bind to a peptide-MHC complex they are brought into proximity. As a consequence CD3 and the \zeta-chains are then close to CD8. On the other hand the kinase Lck is associated to CD8. Thus Lck is brought into proximity with the proteins of the T cell receptor complex and can phosphorylate them. I had never seen this described in detail in the literature. Now I found a review article by van der Merwe and Dushek (Nature Reviews in Immunology 11, 47) which explains this mechanism (and gives it a name, co-receptor heterodimerization) together with a number of other alternatives. It is mentioned that this mechanism alone does not suffice to explain T cell triggering since there are experiments where T cells lacking CD4 and CD8 were triggered. The authors of this paper do not commit themselves to one mechanism but instead suggest that a combination of mechanisms may be necessary.

I will describe one other mechanism which I find particularly interesting and which I already mentioned briefly in a previous post. It is called kinetic segregation and was proposed by Davis and van der Merwe. One way of imagining the state of a T cell before activation is that Lck is somehow inactive or that the phosphorylation sites relevant to activation are not accessible to it. A different picture is that of a dynamic balance between kinase and phosphatase, between Lck and CD45. Both of these enzymes are active and pushing the system in opposite directions. In an inactivated cell CD45 wins this struggle. When the TCR binds to an antigen on an antigen-presenting cell the membranes of the cells are brought together and there is no longer room for the bulky extracellular domain of CD45. Thus the phosphatase is pushed away from the TCR complex and Lck can take control. This could also represent a plausible mechanism for the function of certain artificial constructs for activating T cells, as discussed briefly here.

This mechanism may be plausible but what direct evidence is there that it really works? Some work which is very interesting in this context is due to James and Vale (Nature 487, 64). The more general basic issue is how to identify which molecules are involved in a particular biochemical process and which are not. The method used by these authors is to introduce selected molecules (including T cell receptors) into a non-immune cell and to see under what circumstances triggering can occur. Different combinations of molecules can be used in different experiments. With these techniques it is shown that the kinetic segregation mechanism can work and more is learned about the details of how it might work.

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