PROGRAM IN IMMUNOLOGY 
The Immunology Program is one of the original 
disciplinary areas of the Institute. Studies of the im- 
mune system have led to remarkable recent progress 
in understanding its development, its unique recog- 
nition mechanisms, and the means employed to rid 
the body of invaders or to neutralize potentially 
harmful effects. 
Investigators in the Immunology Program are lo- 
cated at the University of Michigan, the University of 
Alabama at Birmingham, the Massachusetts Institute 
of Technology, Children's Hospital in Boston, the 
University of Texas Southwestern Medical Center at 
Dallas, the National Jewish Center for Immunology 
and Respiratory Medicine at Denver, the University 
of California at Los Angeles and at San Francisco, 
Yale University, Alben Einstein College of Medicine 
of Yeshiva University in the Bronx, Rockefeller Uni- 
versity, Stanford University, the California Institute 
of Technology, the University of Washington in Seat- 
tle, and Washington University in St. Louis. 
Research in the laboratory of Assistant Investiga- 
tor David G. Schatz, Ph.D. (Yale University) focuses 
on understanding the process by which the immune 
system recognizes and neutralizes invading patho- 
gens. Foreign substances are bound by antibodies 
and the T cell receptors that are found on the surface 
of immune system cells (lymphocytes) . The key to 
the effectiveness of the immune system is that each 
of the many millions of lymphocytes expresses a dif- 
ferent antibody or T cell receptor. Each of these re- 
ceptors in turn is encoded by a different gene, and 
each gene is generated by a gene-shuffling process 
known as V(D)J recombination. This process cuts 
and splices DNA within the developing lymphocyte 
to create the millions of different gene combina- 
tions required to encode the receptors. Dr. Schatz's 
laboratory is interested in identifying the enzyme 
that carries out V(D)J recombination, determin- 
ing how this enzyme works, and understanding 
how the process is regulated during lymphocyte 
development. Dr. Schatz and his colleagues had 
previously identified and isolated two genes (the 
recombination-activating genes, RAG- 1 ?LndRAG-2) 
that appear to encode critical components of this 
enzyme. His laboratory now hopes to understand why 
the gene-shuffling process sometimes erroneously 
generates chromosomal translocations, thereby acti- 
vating oncogenes and causing leukemia. Finally, 
they would like to determine if deregulation of, or 
deficiencies in, the V(D)J recombination process 
contribute to immunodeficiency or autoimmunity. 
T lymphocyte activation is controlled by cell sur- 
face proteins that serve as receptors to recognize 
foreign antigens and bind molecules expressed on 
other cells in the immune system. The laboratory of 
Associate Investigator Arthur Weiss, M.D., Ph.D. 
(University of California, San Francisco) has studied 
the biochemical mechanisms by which three recep- 
tors regulate T cell activation: 1) The T cell antigen 
receptor recognizes antigen and activates a protein- 
tyrosine kinase to induce a biochemical cascade of 
events that contributes to cell activation; 2) CD45, a 
membrane molecule, has protein-tyrosine phospha- 
tase activity, an enzymatic activity required for anti- 
gen receptor signaling function; and 3) CD28 binds 
to a molecule on antigen-presenting cells and in- 
duces a distinct signal transduction pathway re- 
quired for inducing lymphokine gene expression. 
Investigator Susumu Tonegawa, Ph.D. (Massachu- 
setts Institute of Technology) and his colleagues 
produced several mutant mice, of which each has a 
defect in an antigen-recognizing molecule ex- 
pressed on the surface of T lymphocytes (T cell 
receptors) or in other genes of immunological sig- 
nificance. Using these mice, they dissected the pro- 
cesses by which T lymphocytes differentiate from 
the immature state to the mature, functional state. 
They also showed that a particular T lymphocyte 
subset, 75 T cells, plays protective roles against bac- 
terial and parasitic infections. The laboratory also 
produced a mutant mouse deficient in an enzyme 
(ct-calcium/calmodulin-dependent kinase) rich in 
the synapses of the hippocampus and neocortex of 
the mammalian brain, and demonstrated that the de- 
fect in this single gene causes an impairment in 
learning the multiple geographical relationships 
among objects in space. 
In the hematopoiesis process, stem cells give rise 
to different types of mature blood cells, including 
the white cells of the immune system. Assistant In- 
vestigator Stephen T. Smale, Ph.D. (University of 
California, Los Angeles) and his associates study the 
molecular mechanisms by which specific genes are 
turned on and off as white blood cells develop to 
maturity. They have identified the LyF-1 protein, 
which appears to turn on several genes in the imma- 
ture white cells by interacting with the genes' con- 
trol regions. In addition, they have identified and 
characterized other features that are unique to the 
control regions of genes expressed specifically in 
developing white cells. 
Associate Investigator Stanley J. Korsmeyer, M.D. 
IMMUNOLOGY 297 
