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
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
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
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
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
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.