Molecular Basis of Lymphocyte Signaling 
Roger M. Perlmutter, M.D., Ph.D. — Investigator 
Dr. Perlmutter is also Professor of Immunology, Medicine, and Biochemistry at the University of 
Washington 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 internal medicine at 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 
enzyme, similar in structure to proteins known to 
transmit growth-promoting signals in nonlym- 
phoid cells, that modifies the behavior of target 
proteins by catalyzing the addition of phosphate 
groups onto certain tyrosine amino acids in sub- 
strate proteins. The gene that encodes this lym- 
phocyte-specific kinase was identified by virtue 
of its overexpression in a murine lymphoid malig- 
nancy. Moreover, we were able to demonstrate 
that a single point mutation in this Ick gene en- 
abled it to confer malignant properties on cells 
maintained in culture. Thus the Ick gene encodes 
a protein that is capable of altering the growth 
properties of at least some cell types. Since Ick is 
normally 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 Ick-cncoded 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 pro- 
tein-tyrosine kinases that are specifically ex- 
pressed in immune cells. In each case there is 
reason to believe that the kinase is physically 
coupled to a cell surface receptor involved in im- 
mune 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 inhibi- 
tion of the function of the Ick gene completely 
disrupts normal mechanisms that permit develop- 
ment of T lymphocytes. In fact the level of Ick- 
encoded protein must be maintained within a 
very narrow range. Even very modest (twofold) 
changes in the abundance of this kinase are in- 
compatible with normal T lymphocyte develop- 
ment. These observations probably reflect the 
fact that the /cfe-encoded kinase participates in a 
large number of receptor signaling pathways, 
including some pathways that are activated 
by lymphocyte-specific growth factors such as 
interleukin-2. 
Disturbances in lymphocyte signaling almost 
certainly contribute to the pathogenesis of lym- 
phoproliferative and immunodeficiency diseases 
in humans. A detailed understanding of immune 
cell signaling mechanisms should permit the de- 
sign of more-effective therapeutic strategies for 
the treatment of immune system dysfunction. 
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