The phosphorylation/dephosphorylation of par- 
ticular protein-tyrosine residues is a remarkably 
potent, reversible modification by which cells 
regulate signal transduction, differentiation, and 
proliferation. The homeostatic balance controlling 
the state of phosphorylation is maintained by the 
coordinate regulation of protein-tyrosine kinases 
and protein-tyrosine phosphatases. The research in- 
terests of Assistant Investigator Matthew L. Thomas, 
Ph.D. (Washington University) and his colleagues 
are in understanding how protein-tyrosine phospha- 
tases function to regulate lymphocyte activation and 
proliferation. Identification and characterization of 
hematopoietic phosphatases have revealed enzymes 
potentially involved in regulating various steps of 
lymphocyte behavior. Functional dissection of the 
major transmembrane phosphatase of lymphocytes, 
CD45, has indicated that this enzyme controls 
antigen-induced activation by regulating the activity 
of Src-tyrosine kinase family members. 
Antibody genes are encoded in pieces in the 
germline and must be assembled during develop- 
ment of antibody-producing cells. The laboratory of 
Investigator Frederick W.Alt, Ph.D. (Children's Hos- 
pital, Boston) has provided fundamental insights 
into the mechanism of this gene assembly process 
and the manner by which its specificity is con- 
trolled. Most recently, this group has employed 
novel approaches to generate mice with several dif- 
ferent mutations that affect particular aspects of the 
development of the immune system. Such mice will 
be invaluable for ongoing studies of the immune 
system's function, and some will also serve as mod- 
els for certain immunodeficiency diseases. 
Investigator Mark M. Davis, Ph.D. (Stanford Uni- 
versity) and his colleagues are exploring the nature 
by which a T cell distinguishes self from non-self 
entities. One aspect of this work is to express spe- 
cific T cell receptors (the equivalent of antibodies 
for the T cell arm of the immune system) implanted 
in mice and observe how they react and develop in a 
particular genetic background. This work has shown 
how T cell receptors that might trigger autoimmu- 
nity are either removed in the thymus or paralyzed 
in the peripheral immune organs if they survive thy- 
mic selection. Many other T cell receptors are dis- 
carded in the thymus because they do not fit that 
particular animal's complement of histocompatibil- 
ity molecules. The laboratory is also expressing 
large quantities of T cell receptors and their target 
histocompatibility molecules free of the cell mem- 
brane in order to reduce T cell recognition to its 
essential components in a cell-free system. 
The analysis of basic properties of CD4 T cells in 
the laboratory of Investigator Charles A. Janeway, Jr . , 
M.D. (Yale University) has provided information 
about the ligands, the specific receptors, the co- 
receptors, and the co-stimulators needed to induce 
CD4 T cell activation. These technologies and prin- 
ciples are applied to the analysis of disease models. 
Studies in future years are intended to extend these 
techniques to problems of autoimmunity and in- 
fectious disease, while continuing to expand knowl- 
edge of basic immune processes. 
The major research interest of Associate Investiga- 
tor Dan R. Littman, M.D., Ph.D. (University of Cali- 
fornia, San Francisco) and his colleagues is in the 
mechanism of differentiation of T lymphocytes. In 
the thymus, these cells undergo a process of selec- 
tion that eliminates potentially self-reactive T cells 
and expands cells that can recognize foreign anti- 
gens. This laboratory is studying the functions of 
surface molecules whose signals contribute to the 
choice of development of functional helper or cyto- 
toxic cells. One of these molecules, CD4, is neces- 
sary, but not sufficient, as a receptor for entry of the 
human immunodeficiency virus (HIV) into cells. 
Several approaches are being employed to identify 
other cellular factors involved in HIV entry. In addi- 
tion, transgenic mouse systems are being used to 
elucidate the mechanism of immunopathogenesis of 
HIV. Information gained from these studies may al- 
low the design of agents that interfere with HIV in- 
fection and pathogenesis. 
Studies in the laboratory of Associate Investigator 
H. Kim Bottomly, Ph.D. (Yale University) span the 
development and peripheral differentiation of sub- 
sets of lymphocytes and extend from studies of acti- 
vation in vivo by specific antigens to detailed analy- 
sis of specific molecular changes that accompany 
these differentiative events. The overall goal of 
these studies is to understand the mechanisms by 
which the immune system generates the appropriate 
effector cells to defend against the different forms of 
pathogens that beset the vertebrate host, as well as 
those cases in which an inappropriate response 
leads to a failure in host defense or an attack on self 
tissues. 
Associate Investigator B. Matija Peterlin, M.D. 
(University of California, San Francisco) and his col- 
leagues study the expression of proteins that help 
fight infectious diseases and cancer and that prevent 
organ transplantation. These are the transplantation 
antigens. Their congenital absence results in severe 
immunodeficiency and early death. Investigated are 
signals that direct the synthesis of these transplanta- 
tion antigens in development and in organs and 
genes responsible for this rare inherited human im- 
IMMUNOLOGY 299 
