Molecular Basis of Lymphocyte Signaling 
Roger M. Perlmutter, M.D., Ph.D. — Associate Investigator 
Dr. Perlmutter is also Professor of Immunology, Medicine, and Biochemistry at the University of Wash- 
ington School of Medicine. He received his B.A. degree from Reed College and his M.D. and Ph.D. degrees 
from Washington University, St. louis, where he studied with Joseph Davie. After clinical training in in- 
ternal medicine at the Massachusetts General Hospital, Boston, and the University of California, San 
Francisco, he became Senior Research Fellow and later Instructor in Biology at the California Institute of 
Technology, where he worked with Lee Hood. 
IMMUNE recognition of potentially injurious 
foreign macromolecules requires the elabora- 
tion of an enormous repertoire of clonally re- 
stricted receptors (antigen receptors) on the sur- 
faces of lymphoid cells. These receptors are 
sufficiently heterogeneous to permit recognition 
of virtually the entire universe of infectious or- 
ganisms. Interaction of these receptors with cog- 
nate antigen provokes a stereotyped response 
leading to cell proliferation and the production 
of soluble mediators of inflammation. During the 
past several years, analysis of the mechanisms re- 
sponsible for antigen receptor diversification has 
stimulated interest in a related question: How is 
the signal from a lymphocyte antigen receptor 
transmitted to the cell interior? Our laboratory 
has adopted a molecular genetic approach to the 
dissection of signaling pathways in immune cells. 
Initially we identified a lymphocyte-specific 
en2yme that is similar in structure to proteins 
known to transmit growth-promoting signals in 
nonlymphoid cells. This protein kinase modifies 
the behavior of target proteins by catalyzing the 
addition of phosphate groups onto specific tyro- 
sine amino acids in substrate proteins. The gene, 
Ick, that encodes this lymphocyte-specific kinase 
was identified by virtue of its overexpression in a 
murine lymphoid malignancy. Moreover, we 
were able to demonstrate that a single point mu- 
tation in the Ick gene was sufficient to unmask its 
ability to deregulate the growth of cells grown in 
tissue culture. Thus the Ick gene encodes a pro- 
tein that is capable of altering the growth proper- 
ties of at least some cell types. Since Ick is nor- 
mally expressed only in lymphocytes, there is 
reason to believe that its product assists in regu- 
lating lymphocyte proliferation. 
Biochemical studies support this view. In par- 
ticular, we and others have recently demon- 
strated that the /c>fe-encoded kinase is physically 
associated with proteins that form part of the an- 
tigen receptor on T lymphocytes. Our studies 
also enabled us to identify two additional protein 
tyrosine kinases that are specifically expressed in 
immune cells. In each case there is reason to be- 
lieve that the kinase is physically coupled to a 
cell surface receptor involved in immune 
recognition. 
To investigate the functional importance of 
these protein tyrosine kinase signaling elements, 
we have developed methods for manipulating the 
expression of each gene in its appropriate cellu- 
lar context. Using this approach, we have begun 
to dissect the hierarchy of signal transduction 
events precipitated by normal immune recogni- 
tion. For example, we found that overexpression 
of an activated Ick gene leads to extraordinarily 
rapid development of thymic tumors in mice. 
Hence altered expression of the Ick gene can di- 
rectly affect lymphocyte proliferation. In a re- 
lated series of experiments we learned that aug- 
mented expression of a protein kinase encoded 
by the fyn gene produced lymphocytes that man- 
ifest 10-fold more vigorous responses to antigen 
stimulation than do normal cells. Interference 
with this ^n-controlled pathway yields cells that 
are refractory to any antigenic challenge. 
Using these and other experimental strategies, 
we hope to deduce eventually a "wiring dia- 
gram" that will adequately describe signal trans- 
duction mechanisms employed by lymphocyte 
antigen receptors. Disturbances in lymphocyte 
signaling almost certainly contribute to the patho- 
genesis of lymphoproliferative and immunodefi- 
ciency diseases in humans. A detailed under- 
standing of immune cell signaling mechanisms 
should permit the design of more effective thera- 
peutic strategies for the treatment of immune sys- 
tem dysfunction. 
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