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T Cell Specificity and Response

Research 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.

Figure 1: Conserved MHC structures...

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. A few years ago, 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).

Recently we have been trying to find out how the body realizes that it has been injected with alum. Alum is given to mice and humans as a very fine particulate suspension. We found, however, that within a few hours of injection into mice, the alum particles are gathered together into large lumps. These lumps contain fibrin, DNA, and histones. Immediately after alum is administered, the body appears to deal with it in the same way it copes with other foreign bodies, such as hip implants or heart valves, by coating it with fibrin. Neutrophils then "attack" the coated particles by disgorging their nuclei, thus capturing the precipitate into fairly large lumps, called NETs. This process, called "netosis" by others, is thought to be a means whereby neutrophils prevent bacteria from moving around the body, and also kill the invaders. Alum will provide a useful model for this process.

Coating of alum with fibrin and the formation of NETs does not seem to play any role in the adjuvant properties of alum. Others have recently suggested that alum acts as an adjuvant by activating a cytoplasmic particle called the inflammasome. We cannot, however, find any role for the inflammasome in the adjuvant assays we use. Also, the Gr1+ cells induced by alum are not required for alum to improve immune responses. However, the Gr1+ cells are needed for alum's well-known ability to bias immune responses toward a TH2-like mode. Thus it is possible that interference with the Gr1+ cells might improve responses to vaccines such as the influenza vaccine, given with alum.

This work is partially supported by funds from the National Institutes of Health and by fellowships from the Leukemia and Lymphoma Society.

As of May 2, 2016

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