Structural and Functional Studies of the T Cell 
Antigen Receptor 
Arthur Weiss, M.D., Ph.D. — Associate Investigator 
Dr. Weiss is also Ephraim P. Engleman Distinguished Professor of Rheumatology and 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 K. 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 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. Our 
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 repre- 
sents a protein fragment that is physically asso- 
ciated with a molecule of the major histocompati- 
bility complex (MHC). 
The TCR is an extraordinarily complex struc- 
ture. It consists of an a//3-chain disulfide-linked 
heterodimer (Ti) derived from immunoglobulin- 
like genes that is noncovalently associated with 
six invariant chains of the CD3 complex and a 
f-chain dimer. CD3 consists of four chains (5-, 7-, 
and two e-chains) derived from three closely 
linked homologous genes located on chromo- 
some 1 1 . The f dimer, derived from the products 
of two homologous genes on chromosome 1 , may 
represent a homodimer (f^ or heterodimer con- 
sisting of fry (77 is an alternatively spiced form of 
f) or (7, a homologous protein, is also a com- 
ponent of the IgfFc receptor on mast cells and 
basophils) . Ti is the ligand-binding subunit of the 
TCR, since it contains all the information needed 
to recognize antigen and MHC specificities. CD3 
and f have been thought to play some role in 
transducing the ligand occupancy state of Ti 
across the plasma membrane. Hence the struc- 
tural basis for the association of Ti, CD3, and f is 
of interest. 
Previous studies from our laboratory have dem- 
onstrated that coexpression of all of the chains of 
the oligomeric TCR — Ti, CD3, and f — on the 
plasma membrane is obligatory for efficient TCR 
expression. Studies from this laboratory demon- 
strated that the structural and functional basis for 
the interaction between Ti, CD 3, and f is con- 
tained within regions including the transmem- 
brane domains of these proteins. Further muta- 
tional studies are in progress to understand more 
precisely how Ti, CD3, and f interact function- 
ally within these domains. 
Since the transmembrane regions are responsi- 
ble for the Ti-CD3-r association, we have taken 
advantage of this information to separate regions 
or domains of CD3 and f from Ti. This has been 
accomplished by constructing chimeric mole- 
cules between other cell surface molecules 
linked to the cytoplasmic domain of TCR chains. 
A chimeric molecule consisting of the CDS extra- 
cellular and transmembrane domains fused to 
the f cytoplasmic domain acquired the signal- 
transducing capacity of the entire TCR. This find- 
ing demonstrates that the cytoplasmic domain of 
CD3 f can link the TCR to intracellular signaling 
machinery. 
These studies are being extended to define the 
region of f that interacts with such intracellular 
molecules and to identify these molecules. Re- 
cently we identified a 70-kDa tyrosine phospho- 
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