the TCR induces several intracellular biochemical 
changes. The relationship between these changes 
and cellular responses has been revealed by experi- 
ments in which a foreign receptor has been intro- 
duced into a T cell line. The receptor for the neuro- 
transmitter acetylcholine, normally expressed on 
nerve or muscle cells, was introduced into a T cell 
line. Stimulation of these T cells with acetylcholine 
induces well-characterized biochemical signals that 
are also induced by the TCR. These biochemical 
changes result in the activation of the T cell line, as 
measured by the secretion of lymphokines (hor- 
mones of the immune system) arid expression of 
new growth factor receptors. Thus the signals that 
these two receptors both induce can lead to T cell 
activation. How the TCR induces these changes is 
not known. In an attempt to elucidate this process, 
a genetic approach has been used to isolate mu- 
tants of a T cell line that fail to respond to TCR 
stimulation. This laboratory also has identified two 
proteins that interact with the TCR after it has been 
stimulated. By characterizing the nature of these 
mutations and the molecules that interact with the 
TCR, insight into how T lymphocytes become acti- 
vated to express their functional activities should 
emerge. This may lead to more rational approaches 
to regulating T cell activities in disease states. 
The laboratory of Associate Investigator Mark M. 
Davis, Ph.D. (Stanford University) has developed a 
model of T cell recognition that could help to ex- 
plain why the antigen receptors on T cells differ so 
dramatically from those on B cells. The model also 
suggests how antigen receptor genes could have 
evolved from more primitive cell surface molecules. 
The establishment of lines of mice carrying and ex- 
pressing specific T cell receptor complexes prom- 
ises to yield important information on receptor se- 
lection and control of expression during T cell 
development in the thymus. 
Investigator Susumu Tonegawa, Ph.D. (Massachu- 
setts Institute of Technology) and his colleagues 
have continued to study the nature and function of 
T cells bearing the second type of receptor, 78 TCR. 
They found that these T cells are localized in many 
epithelial tissues, including those in the reproduc- 
tive and digestive organs. The TCR expressed in 
some of the epithelia are structurally undiversifled, 
while those expressed in others are diverse. This 
laboratory also showed that a DNA element associ- 
ated with the TCR 7 gene plays a critical role in the 
cell lineage determination of ap and 78 T cells. A 
definition of the nature of the molecules (ligands) 
recognized by 78 T cells is also sought. 
Lymphocyte interactions during an immune re- 
sponse are necessary for the activation of antigen- 
specific lymphocytes. The resulting effector phase 
of an immune response is described as being either 
humoral or cell mediated. These effector mecha- 
nisms are well characterized, yet the precise mecha- 
nisms by which the response to a given antigen or 
infectious agent is directed into the humoral or 
cell-mediated mode are not known. What is clear, 
however, is that both types of immunity depend on 
the activation of CD4 T cells, which were originally 
shown to have multiple functions, including help- 
ing B cells proliferate and secrete antibody, me- 
diating delayed-type hypersensitivity reactions, pro- 
liferating in vitro to exogenous antigens, and 
inducing CDS cytolytic T cells. Thus it was ques- 
tioned whether the same CD4 T cell could mediate 
all these functions, thus encompassing both hu- 
moral and cell-mediated responses, or whether the 
CD4 T cell population was functionally heteroge- 
neous. CD4 T cell functional heterogeneity and the 
activation conditions that lead to this heterogeneity 
have been a central focus of the laboratory of Asso- 
ciate Investigator Kim Bottomly Ph.D. (Yale Uni- 
versity). 
The major research interest of Assistant Investiga- 
tor Dan R. Littman, M.D., Ph.D. (University of Cali- 
fornia at San Francisco) is the function of the T cell 
surface molecules CD4 and CDS. These molecules 
bind to different types of histocompatibility mole- 
cules and transmit signals required for the choice of 
developmental pathways during thymocyte devel- 
opment. Dr. Littman's laboratory is studying the 
molecular basis of the interaction of CD4 and CDS 
with the histocompatibility molecules, with T cell 
receptors, and with intracellular protein kinases in- 
volved in transducing signals. The CD4 molecule 
also serves as the major receptor for the human im- 
munodeficiency virus (HIV). Genetic and structural 
approaches are being used to study the basis of the 
interaction of CD4 with the HIV envelope protein. 
Genetic approaches are also being employed to 
identify other receptors involved in HIV entry. In- 
formation gained from these studies may allow de- 
sign of derivatives of these receptors that can inter- 
fere with HIV infection. 
The laboratory of Investigator Warner C. Greene, 
M.D., Ph.D. (Duke University) also studies the mo- 
lecular and biochemical basis for the activation and 
growth of cells that form the body's immune de- 
fense. Recent attention has focused on various dis- 
ease-causing viruses that interrupt this defense net- 
work, including human retroviruses that cause 
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