Structural and Functional Studies of the T Cell 
Antigen Receptor 
Arthur Weiss, M.D., Ph.D. — Associate Investigator 
Dr. Weiss is also Associate Professor of Medicine and of Microbiology and Immunology at the University of 
California, San Francisco. He received his undergraduate education at the Johns Hopkins University and 
was an M.D./Ph.D. student at the University of Chicago, where he studied immunology in the laboratory 
of Frank Fitch. He did postdoctoral work with Jean-Charles Cerottini and Theodore Brunner at the Swiss 
Institute for Experimental Research, Lausanne. After an internship and residency in internal medicine at 
UCSF, he became a postdoctoral fellow in rheumatology with John Stobo. 
THE immune system has evolved to provide an 
organism with a flexible and dynamic mecha- 
nism to respond specifically to a wide variety of 
antigens. During the initiation of an immune re- 
sponse, antigen must not only be recognized by 
antigen-specific lymphocytes, but this recogni- 
tion event must lead to a cellular activation. T and 
B lymphocytes comprise the antigen-specific 
components of the cellular immune system. The 
activation of T lymphocytes is critical to most im- 
mune responses, since it permits these cells to 
exert their potent regulatory or effector activi- 
ties. During activation, relatively quiescent cells 
undergo complex changes involving cell differ- 
entiation and proliferation. 
Following exposure to antigen, activation of T 
lymphocytes is limited to only those cells ex- 
pressing antigen-specific receptors. Activation is 
a consequence of ligand-receptor interactions 
that occur at the interface of the T cell and an 
antigen-presenting cell. These interactions initi- 
ate intracellular biochemical events within the T 
cell that culminate in cellular responses. The 
goal is to understand how cell surface molecules 
on the T cell, and in particular the T cell antigen 
receptor (TCR), initiate T cell activation. 
Although it is clear that a number of different 
cell surface molecules on the T lymphocyte and 
the antigen-presenting cell may participate in the 
complex cell-cell interaction that occurs during 
antigen presentation, the TCR must play a promi- 
nent role. Here the familiar lock and key analogy 
is appropriate. Antigen is the ligand (key) for a 
particular set of clonally distributed receptors 
(locks) on T lymphocytes. Antigen often rep- 
resents a protein fragment that is physically 
associated with a molecule of the major histocom- 
patibility complex (MHC) . The TCR is an extraor- 
dinarily complex structure. It consists of an a//3- 
chain disulfide-linked heterodimer (Ti) derived 
from immunoglobulin-like genes that is noncova- 
lently associated with the six invariant chains of 
the CD 3 complex. Ti may be viewed as the li- 
gand-binding subunit of the TCR, since it con- 
tains all the information needed to recognize an- 
tigen and MHC specificities. CD3 has been 
thought to play some role in transducing the li- 
gand occupancy state of Ti across the plasma 
membrane . Hence the structural basis for the asso- 
ciation of CD3 and Ti is of interest. 
Previous studies from our laboratory have dem- 
onstrated that coexpression of CD3 and Ti on the 
plasma membrane is obligatory. In recent stud- 
ies, we have found that the structural and func- 
tional basis for the interaction between Ti and 
CD3 is contained within the transmembrane do- 
mains of these proteins. Further mutational stud- 
ies are in progress to understand more precisely 
how Ti and CD3 interact functionally within 
these domains. 
Since the transmembrane regions are responsi- 
ble for the Ti-CD3 association, we have taken ad- 
vantage of this information to separate regions or 
domains of the CD3 chains from Ti. This has been 
accomplished by constructing chimeric mole- 
cules between other cell surface molecules 
linked to the cytoplasmic domain of the CD3 
chains. Chimeric molecules including the CD3 
f-chain acquire the signal-transducing capacity of 
the entire TCR. These results demonstrate that 
the cytoplasmic domain of CD3 T links the TCR to 
intracellular signaling machinery. The ability to 
create such functional chimeric receptors may 
permit the creation of new antiviral or antitumor 
TCRs, which may be valuable in gene therapy. 
The interaction of the TCR with its ligand, anti- 
gen/MHC, initiates cellular activation by induc- 
ing a transmembrane signal. Such signal trans- 
duction is manifested as the formation of 
intracellular biochemical mediators called sec- 
ond messengers, which can initiate or influence 
cellular response pathways. The TCR activates 
two signal transduction pathways. One signal 
transduction mechanism, the inositol phospho- 
lipid pathway, involves receptor-stimulated hy- 
drolysis of a rare membrane lipid, PIP2 (phospha- 
tidylinositol 4,5-bisphosphate). This yields two 
potent intracellular second messengers (inositol 
1 ,4,5-trisphosphate and diacylglycerol), which 
regulate the mobilization of the enzyme protein 
kinase C. These latter two events are physiologi- 
cally important to subsequent cellular responses. 
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