"We would like to know what antigens are involved in autoimmune diseases," says Philippa Marrack of the National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado. Marrack is shown above with her husband and collaborator John W. Kappler.

   Because of their role in helping humans and other vertebrates to recognize and fight off invading organisms, T cells play a major role in biomedical research. T cells that carry alpha-beta receptors spot the arrival of foreign material in the body; in response, the cells divide, creating other T cells. These, in turn, help to produce antibody and cytotoxic cells, which can destroy the invading material. To work efficiently, T cells must recognize all sorts of alien organisms, but must not react to material from their own host. Biomedical scientists believe that a failure of the second criterion lies at the root of autoimmune diseases such as arthritis, multiple sclerosis, and juvenile diabetes.

   Not surprisingly, the study of T cells has become a hot topic in biomedical laboratories. A major objective of several research groups is to discover how the host deals with T cells that have the potential to turn against it and cause autoimmune conditions. Both theory and experiment indicate that host animals must produce T cells that can react with the host itself, in addition to cells that can react with a variety of invading organisms. So the question arises: Why does not every animal suffer autoimmune disease caused by those particular cells?

   Over the past 15 years, several papers on this and other mysteries of T cell functions have carried the author's name P. Marrack. British-born Philippa Marrack earned her initial degree in molecular biochemistry from Cambridge University, and followed that up with a Ph.D. in biological sciences, which she completed in 1970, at the Medical Research Council Laboratory for Molecular Biology in Cambridge. After post-graduate work with Richard Dutton at the University of California, San Diego (UCSD), she moved to the University of Rochester. Seven years later, Marrack went to Denver. There, she is an investigator with the Howard Hughes Medical Institute, a member of the Department of Medicine at the National Jewish Center for Immunology and Respiratory Medicine, and distinguished Professor of Biochemistry, Biophysics, and Genetics and of Immunology and Medicine at the University of Colorado Health Sciences Center. A member of the National Academy of Sciences, Marrack recently received the Wellcome Foundation Prize of the Royal Society and the Paul Ehrlich and Ludwig Darmstaedter Award of the Paul Ehrlich Foundation.

   Marrack, in fact, makes up one half of a husband-and-wife team that is tracking the mystery of T cells. She has carried out most of her work in collaboration with her husband, John W. Kappler. Both researchers were featured prominently last spring in a survey of highly cited scientists in immunology (see Science Watch, 6(5):1-2, May 1995). Marrack recently talked with special correspondent Peter Gwynne.

            Your work has largely involved T cells. What got you interested in them originally?

   Marrack: When I decided to do a Ph.D., I was going to do something different. But I met my future thesis adviser, Alan Munro, at a cocktail party, and he sort of seduced me into working in his lab. T cells had just been recognized to exist by Jacques Miller of the Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia, and others. So Alan set me to work to set up some cultures for the cells. Very luckily, the cells were very interesting. They turned out to be different from what we had expected and significant in all sorts of human diseases. Also, they've never stopped being useful sources of information about cell biology and eukaryotic genetics. T cells are the Human Genome Project of the cell world.

            You said that the T cells were related very strongly to a spectrum of human diseases. How closely has your work paralleled advances in understanding human diseases, and how much has it stimulated that understanding?

   Marrack: The basic scientific discoveries have made a tremendous difference to our understanding of human diseases. For example, in the early '70s Hugh McDevitt of Stanford University and Walter Bodmer of the Imperial Cancer Research Fund, London, were the first to recognize that autoimmune diseases were genetically linked to the major histocompatibility complex (MHC) genes. At the time, scientists had no idea what this meant. Later it was shown that T cells have the peculiar property of seeing foreign material only when that material is associated with MHC proteins. This finding provided the clue as to what the linkage between autoimmune disease and MHC might be--that in autoimmune diseases T cells are somehow inappropriately recognizing material from their own host, bound to the host's MHC proteins. It was this kind of realization that has propelled most of the recent medical advances in treating disease that had not even previously been universally recognized to be due to autoimmunity, such as multiple sclerosis. The crucial discovery in all of this dealt with the way that T cells recognize foreign material (antigens). Five pieces of work led to the understanding: the discovery of the T cell receptor protein by ourselves and others; the discovery of the T cell receptor genes by Steven Hedrick, Mark Davis, and Tak Mak, now at UCSD, Stanford, and the Ontario Cancer Institute; the finding that T cells recognize foreign material associated with MHC proteins, by Rolf Zinkernagel and Peter Doherty, then at the John Curtin School in Canberra, Australia; the recognition that T cells recognize fragments of foreign material--peptides, not intact proteins--by Emil Unanue of Washington University, St. Louis, and Howard Grey at the National Jewish Center; and finally the resolution of the actual structure of MHC proteins by Pam Bjorkman, Don Wiley, and Jack Strominger at Harvard.

            What have been the key advances along the way?

   Marrack: The recognition of how T cells recognize antigens was a key to understanding autoimmune diseases. The next key came from theory. For many years we knew that even though T cell receptors are randomly made, and therefore should be able to react with a random collection of peptides and MHC, T cells do not recognize the animals' own cells in healthy animals. This is true even though, in an uninfected animal, the MHC proteins on the animal's own cells have between 2,000 and 20,000 of the animal's own peptides bound to them. Even though the animal can make a random collection of T cell receptors and has a random collection of its own peptides bound to MHC, the T cells in that animal do not attack its own cells. For a long time immunologists tried to understand how this could be. In the 1950s, Joshua Lederberg of the Rockefeller University suggested that binding to immature cells causes them to die. The alternate idea, from Australia, put forward by Sir Gus Nossal at the Hall Institute, was that T cells would not die, but would be inactivated in a young phase. There was also a theory that there would be a network of cells reacting with each other to suppress others. It was very difficult to tell the difference between them, as it was difficult to tell if the cell was there unless it divided.

            So it had to do something--in other words, divide--to bring itself to your attention. What happened then?

   Marrack: We had a tremendously lucky break. We found a group of antigens that reacted with a tremendous number of T cells. We called them superantigens. Using them, we could tell whether T cells that would react with them were present and what the T cells were doing. In mice which contained superantigens throughout their lives, the T cells which could react with these superantigens were missing; they disappeared before they got out of the thymus. This was unequivocal proof of Lederberg's theory.

            So in order for autoimmune cells to be screened out, the T cells have to go through the thymus and be exposed to self-antigens, which cause the autoimmune cells to die. If that doesn't happen for some reason or other, then autoimmune T cells can come out of the thymus and attack their host. What came next?

   Marrack:This discovery helped the field of autoimmunity tremendously. And this process of thymus death doesn't seem to go wrong; it's very efficient. But proteins from some cells don't go through the thymus to cause the death of T cells which can recognize them. This may lead to autoimmunity, which not surprisingly seems to target some relatively sequestered organs, like the brain and the eye.
   A lot of investigators (not including ourselves) demonstrated that you could find T cells that could react with brain and joint cells in normal humans and mice. So the question is: Why don't we all become autoimmune?--not: Why do some people become autoimmune? Clearly there must be some ways of overcoming autoimmunity. We're looking into why. This is now our general line of work.

            What, specifically, are you looking at?

   Marrack: Shigekazu Nagata of the Osaka Bioscience Institute, Japan, and Peter Krammer in Heidelberg, Germany, discovered the protein Fas. This is a cell surface protein which, when it is bound by its ligand, signals the cell bearing it to die. It has been found that activated T cells express Fas and bear Fas on their surfaces. These cells are therefore vulnerable to death and, in many cases, will die. It is thought that this is the fate of most of the T cells in our bodies that can react with our own proteins. This is a great hypothesis, but it doesn't explain how we cope with disease. It doesn't explain how proper immune responses will ever occur. In other words, if activated T cells are all destined to die, how does an immune response against an infection ever get off the ground? The current hypothesis is that there is something about the infection itself that bypasses the Fas pathway and other pathways like it. We believe that infections cause inflammatory proteins to be made, and that inflammatory proteins tell lymphocytes: "Even though you've got Fas on your surface, you're not supposed to die." We're trying to find out if this idea is correct.
   These ideas suggest that even a mature T cell can go through a program that makes it die when it meets an antigen, but that something about infections--endotoxins, viruses, bacteria, fungi--turns this process off. If this is true, it suggests to us that people become autoimmune because one of these things associated with infections reaches an unexpected part of the body, such as the brain. If this happens at the same time as a potentially autoimmune T cell reaches the same place, the autoimmune T cell may be allowed to live instead of die, and thus cause an autoimmune disease.
   We would like to know what antigens are involved in these autoimmune diseases. For example, multiple sclerosis may start with a single T cell in the wrong place at the wrong time. Once damage occurs, other T cells get recruited to the site, and cause more damage. Can we find the antigen targets? That's an ongoing question in lots of laboratories studying rheumatoid arthritis, multiple sclerosis, and juvenile diabetes; it's being asked in lots of laboratories. Once we identify target proteins, how can we destroy the T cells that are attacking them? Basic immunology has helped tremendously in allowing scientists to understand the diseases, but it hasn't yet provided cures.

            Can you see ways in which your work can be adapted to attack another serious problem involving the immune system: overcoming the rejection of organ transplants?

   Marrack: I think eventually we will understand how to make a cell die when it meets an antigen, and this may help. For transplants, you could probably pretreat the organ to make it more acceptable, and in fact this is already done. Another possibility is to give multiple blood transfusions before grafting, with the idea of ferreting out ahead of time cells that could attack the graft. This has been done for some years and is quite helpful.

            To turn to broader questions of science policy: How do you feel biomedical research is likely to fare in the next few years, given the budgetary problems the country is going through? Do you think that biomedical research can survive the cuts that will be imposed on it?

   Marrack: I don't know if Congress knows how much education is indirectly funded by the NIH, particularly medical school education. The potential impact of cuts isn't just in what we discover, but in our ability to teach what is already known. If the budget is significantly cut, that's going to make a huge inroad into faculty and teaching. That's going to feed back into the economy. The United States is a leader in biomedical research and technology because of the support it gives research through NIH, NSF, and other agencies. Cuts in the funding of these agencies will affect our ability to continue to spearhead industrial developments in this area. These cuts will also affect our ability to educate our future scientists and medical practitioners properly.