T Cell Receptors
T cells detect their targets by way of their T cell receptors. I've shown a cartoon of this structure in a previous post. Recall that it consists of two chains, alpha and beta, that each bear a variable and constant region. Like their B cell counterparts, T cell receptors can assume enormous diversity in sequence due to random recombination of their variable gene segments. However, the T cell receptor doesn't refine its binding site after activation like the B cell receptor. Nor is there switching of constant regions. And, as I've already mentioned, the T cell receptor only binds to peptides that are affixed to the MHC. A model of the T cell receptor bound to a peptide that is being presented by a MHC is shown at the right. The molecular modelling program, Chimera, was used to generate the picture.
There are several other parts to the T cell receptor aside from the peptide recognition chains shown in blue in the figure above. In fact there are six additional protein chains that associate with the alpha and beta chains. They function to signal the inside of the cell that the recognition part has found a target. When properly stimulated, they signal to the cell nucleus to begin synthesizing the appropriate molecules that "activate" the various kinds of T lymphocytes so that they can begin fulfilling their functions. I'll discuss what these functions are in a subsequent post. For now I'll discuss the mechanism of the activation process.
The first step in T cell activation is binding of its receptor to a MHC borne antigen. Previously I mentioned that almost all cells have MHC I proteins on their surface and many have MHC II's. But naive T cells, ones that haven''t ever encountered their cognate antigens, can not be activated by any old MHC-bearing cell. Activation requires that they interact with what immunologist have quaintly termed a "professional" antigen presenter. There are three kinds of these professional cells, but one is most important. And it's one that we've encountered previously in the innate immune system: the dendritic cell.
Dendritic cells are located all over the body. In the absence of a microbial invader they assume a resting state, and, as such, are not very good at activating T cells. But they keep one eye open for trouble. Using their pattern recognition receptors they can detect an attack that is directed on them. Or they can react to an indirect attack on a neighbor by responding to chemicals given off by cells that are in distress. They also can respond to cytokines secreted by macrophages and neutrophils (remember them?). All of these situations result in dendritic cell activation. Yes, that's right. Dendritic cells must be activated before they, in turn, can activate T cells.
The results of this activation are profound. The dendritic cells begin a journey to the nearest lymph node. As they move they transfer additional peptide-loaded MHC I and II molecules to their cell surfaces. In addition, dendritic cells begin to mobilize several surface proteins (co-stimulators) that are complementary to receptors on the surface of T cells. When they reach their destination they encounter numerous T cells. If a T cell with the appropriate receptor encounters an activated dendritic cell presenting a corresponding peptide and co-stimulators, the two cells will cozy up to each other. It is the junction between the two cells when they are in close proximity that activates the T cell. A portrait of their embrace is shown.
There is one additional feature of T cell/dendritic cell interaction that I haven't explained. It has to do with the protein labelled "CD4 or CD8" in the diagram. I will discuss this matter along with the role of activated T cells in the next post.