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T Cell Specificity and Response
Summary: Philippa Marrack is interested in the creation, specificity, survival, and activation of T cells.
Our laboratory studies the specificity, survival, and function of T cells bearing αβ T cell receptors (TCRs). These are the cells that orchestrate the specific immune response to antigens and that usually react with peptides derived from antigens bound to major histocompatibility complex (MHC) proteins on the surfaces of cells.
For a long time immunologists have tried to understand why TCRs are so obsessed with MHC proteins. One possibility is that the genes that code for TCRs have been selected during evolution to have some intrinsic affinity for MHC proteins. On the other hand, T cells can only mature properly if their receptors have some ability to react with low avidity with MHC proteins that are present in the thymus. Thus, TCRs might have completely random specificities, but because of this selection in the thymus, only cells bearing receptors that have some affinity for MHC are allowed to survive. These two ideas are not mutually exclusive. Both hypotheses might be at play and together focus the attention of T cells on MHC.
The idea that TCRs have been selected evolutionarily to react with MHC makes several predictions possible. First, when these receptors bind MHC, they should do so in some predictable way, with particular amino acids of the TCRs consistently contacting particular amino acids of MHC. Second, these interactions should allow TCRs to bind many of the different MHC proteins of the species. Neither prediction has been supported by previous experiments.
We realized that the receptors on mature T cells in normal animals have been culled to remove receptors that react well with MHC and that would therefore best illustrate the rules built in by evolution. Therefore we screened a set of receptors that had not been so well preselected and found, in x-ray crystallography studies, that these do show consistent binding of certain TCR amino acids to MHC. To find out whether these TCR amino acids are required for the receptors to bind MHC, we have introduced genes coding for mutated versions of these amino acids into mice. The mutant receptors do indeed bind MHC less well, suggesting that the evolutionary idea is correct.
Once lymphocytes mature, they respond to antigen by dividing rapidly. Most of the cells that are thus created then die. Such death is thought to be important to avoid saturating the animal with lymphocytes that have responded to successive waves of different infections. Our experiments suggest that death of these T cells is caused by changes in the ratios within the cell of a set of proteins related to Bcl-2. Bcl-2 and its close relatives prevent death; other proteins, such as Bax and Bak, appear to kill the cell.
Despite this information, and many years of work by many groups, the precise process whereby the Bcl-2 family controls life and death is not known. To take a fresh approach to this problem, we are working on proteins made by viruses that achieve the same end. The hypothesis is that viruses have but one goal, to preserve the life of cells while they (the viruses) reproduce themselves. Thus their Bcl-2-like proteins are probably entirely focused on prevention of cell death, whereas the mammalian analogs may have additional tasks. These additional tasks confuse analysis. With this in mind we work on BHRF1, a Bcl-2-like protein produced by Epstein-Barr virus. Although structural studies by others suggested that this protein could not interact with other Bcl-2-related proteins, our results show that it does. Moreover, quantitation of the results suggests that BHRF1 may act in an unexpectedly catalytic fashion.
Vaccines protect humans and other animals against infections. To work properly, a vaccine must contain not only some portion of the infection—for example, tetanus toxoid—but also an adjuvant, a material that dramatically improves the immune response against the infection and increases the ability of the immune system to remember that it has seen the infectious agent before, in the vaccine. One of the most common adjuvants is alum, a precipitate of aluminum salts. Surprisingly for a reagent that has been given to just about every human being on the planet, we have very little idea about how alum works. Recently, in collaboration with the laboratory of John Cambier (National Jewish Medical and Research Center), we found that alum causes the appearance of a previously unknown collection of cells. These cells are like monocytes but also have some properties of granulocytes and make a potent immune stimulator, interleukin-4 (IL-4).
It is surprising that alum is such an effective adjuvant because, unlike other adjuvants, it does not have an obvious "natural" counterpart. That is, our immune systems have probably not been selected during evolution to regard alum as an indicator of infection. We therefore wondered whether there was a previously unappreciated natural compound that acts like alum and that alum may therefore mimic. The helminths, worms that infect humans and other animals, seemed like candidates for such mimics, since it is known that helminths induce immune responses that are similar to those induced by alum. We have therefore started to compare the properties of alum with those of one version of helminths, eggs of schistosomes. So far the two materials behave identically, with similar induction of the monocyte/granulocyte-like cells that make IL-4, and similar abilities to act on T and B cells.
Recently we have been trying to find out how the body realizes that it has been injected with alum. Alum injection causes the rapid appearance of a specialized type of white blood cell, the eosinophil. Eosinophils are also induced rapidly by schistosome eggs and, to our surprise, by other materials such as aggregated ovalbumin, essentially fragments of boiled egg white. The results suggest that alum may act by partially denaturing proteins of the host and that it is the recognition of the denatured proteins that leads to the downstream adjuvant effects of alum.
Our work is partially supported by funds from the National Institutes of Health and by fellowships from the Leukemia and Lymphoma Society.
Last updated: May 1, 2008
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