dvances in cell biology and basic science are made in step-by-step increments of understanding, achieved over years of painstaking research. While not usually typical headline-grabbing material, such research has led to some of the most important medical achievements of this century, including the development of vaccines that have eradicated once common and deadly diseases. Scientists have long been hoping to develop such vaccines against cancer. Medicine is now a little closer to that goal because of the work of two immunologists to delineate how T-cells recognize foreign or abnormal cells, and to identify the genes that code for the antigen receptors on T-cells.
For their pioneering efforts in basic science, Mark M. Davis, phd, Investigator at The Howard Hughes Medical Institute and Professor of Microbiology and Immunology at Stanford University School of Medicine, and Tak W. Mak, phd, Department of Molecular Biology at The Ontario Cancer Institute, Director, Amen Institute, and Professor of Medical Biophysics at University of Toronto, were jointly honored with the 1996 Alfred P. Sloan Prize, awarded by the General Motors Cancer Research Foundation.
Untangling the Intricacies of T-Cells
T-cells are a major force in the immune system, whether that system is fighting off the common cold or cancer. T-lymphocytes play different roles in combating not only bacterial or viral invaders but also abnormal cells that arise in the body. Helper T-cells first recognize these foreign antigens and then signal B-lymphocytes to pro
can recognize foreign proteins on the surface of an abnormal (eg, virus-infected) cell and destroy it. The role of recognizing foreign proteins falls to foreign protein (antigen) receptors (T-cell receptors) on the T-cell surface.
In the past decade, scientists have been learning more about these antigens and the T-cell receptors that respond to them. Finding the genes that code for these receptors was regarded as the "Holy Grail" of immunology, because knowledge of T-cell receptor gene function is the key to understanding immune reactions and is essential to developing strategies to prevent and treat infectious and autoimmune diseases, as well as cancers.
While a staff fellow at the National Institutes of Health in 1984, Dr. Mark Davis, together with Dr. Stephen Hedrick and others, reported the cloning of a gene that encodes the amino acid sequence that controls a T-cell receptor in mice. Later at Stanford University, Dr. Davis and Dr. Yueh-Hsiu Chien found two other types of T-cell receptor genes found to govern the two major types of T-cell receptors: the alpha-beta receptor and the gamma-delta receptor.
The alpha-beta receptor is the principal receptor occurring on most T-cells in the body. It was found to recognize not only antigens but also a molecule called the major histocompatibility complex (MHC) formed when proteins are degraded as part of normal cell metabolism. The MHC gathers up bits of proteins (called peptides) left behind and displays them on its surface. These peptides include tumor cell-specific peptides.
The Mystery of T-Cells
"Before this, T-cell receptors were a very mysterious part of the immune system. We knew that B-cells recognized foreign entities using antibodies, but we didn't know what T-cells used and how they 'see' both antigen and MHC together," Dr. Davis explains.
Dr. Davis and colleagues have since directed their efforts to understanding how T-cells interact with antigen/MHC protein complexes, which turn out to be involved in almost every human immune response, including the recognition of tumor cells by receptors on killer T-cells. "One of the most exciting areas of cancer research today involves boosting the T-cell response to tumor-related peptides bound to MHC molecules," he adds.
Working independently, Dr. Tak W. Mak and colleagues at the Ontario Cancer Institute and the University of Toronto identified genes for the antigen receptor of human T-cells in 1984, ending a long quest in the immunology community. Dr. Mak's laboratory also detailed the structure and function of T-cell receptors, including the chromosomal locations of the receptor genes, as well as the organization of the gene's segments and their functions.
Using this new-found knowledge, Dr. Mak studied receptor genes in patients with T-cell malignancies, such as leukemia and lymphoma. This approach is now an established method that aids in the diagnosis of these cancers. One of the team's important discoveries was that chromosomal translocations (wherein a piece of one chromosome breaks off and somehow attaches itself to another chromosome) can activate cancer-causing oncogenes. Extensive studies have resulted in the identification of many chromosomal breakpoints and their links to malignancies.
"Designer Genes" and "Knock-Out" Mice
Starting in 1990, Dr. Mak's team developed transgenic mice bred to carry "designer genes" for specific T-cell receptors. Even more useful were the "knock-out" mice, bred to carry mutations that "knocked out," or deleted, a specific immune gene or function. These mice provide models to study gene deletions (which may be inherited or occur during one's lifetime) and immune dysfunction. By studying these mice, Dr. Mak has also gained key insights into the poorly understood process of thymic selection of T-cells, ie, how T-cells "learn" to recognize foreign proteins without destroying "self" proteins. New information on molecules required to assist T-cells in their action, the costimulatory proteins, has also come to light. These results have important ramifications in treating recurrent infections, cancer, autoimmune diseases, and even AIDS.
"Any attempt to create T-cell-mediated immunotherapy for cancer rests on the foundation of Dr. Davis' and Dr. Mak's discoveries," stressed Joseph G. Fortner, md, President of the General Motors Cancer Research Foundation in announcing the joint award. "The T-lymphocyte is centrally involved in our resistance to some cancers. Dr. Davis' and Dr. Mak's work not only clarified the role of the T-cell receptor in immune reactions to cancer, but also the ways in which various substances may affect how the cell behaves. This understanding is very important to the development of vaccines against cancer."
An example is the recently developed vaccine against melanoma, which involves deactivating tumor cells so that they are no longer malignant and then using them to stimulate an immune response in the body. The tumor-destroying killer T-cells are primed to recognize the foreign proteins of the melanoma and attack active malignant melanoma cells. Without the knowledge of how T-cell receptors recognize their targets and how to trigger that response, creating this and future vaccines would have been impossible.
Dr. Davis received his undergaduate degree at Johns Hopkins and earned a PhD in molecular biology from the California Institute of Technology in 1981. He was a postdoctoral and staff fellow at the Laboratory of Immunology at the National Institutes of Health. He was elected to the National Academy of Sciences in 1993.
Dr. Mak, a Canadian citizen, received his bs and ms degrees from the University of Wisconsin, Madison, and his phd in biochemistry from the University of Alberta, Edmonton. He joined the University of Toronto faculty in 1976. In 1994, he was elected fellow of the Royal Society of London.