those cells that recognize their own host tissues 
(autoreactive cells) die, and only those cells that 
are not autoreactive are allow^ed to become fully 
mature and escape into the circulation for distribu- 
tion throughout the body, where they can contrib- 
ute to disease resistance. 
Associate Investigator Dennis Y Loh, M.D. (Wash- 
ington University) and his colleagues are also in- 
terested in thymus-derived lymphocytes. To un- 
derstand how T cells develop under normal 
circumstances, genes important in T cell function 
have been cloned and re-introduced into transge- 
nic mice. Results are providing insights into how T 
cells learn to discriminate self and nonself markers 
to maintain the balance of the body's immune 
system. 
The laboratory of Associate Investigator Roger M. 
Perlmutter, M.D., Ph.D. (University of Washington) 
has defined a limited set of gene segments that con- 
tributes preferentially to the assembly of antibody- 
combining sites during fetal and neonatal life. Many 
of these early antibodies appear to be similar to an- 
tibodies found in patients with autoimmune dis- 
eases, indicating that pathologic autoantibodies 
may be part of the normal preimmune repertoire. 
Other studies have identified protein tyrosine ki- 
nases that behave as signal transduction elements 
in hematopoietic cells. Experiments in cell lines 
and in transgenic animals suggest that one of these 
(p56''^^ participates in signal transduction from the 
T cell antigen receptor complex. 
T cells recognize the presence of foreign mate- 
rial, such as bacteria or viruses, in the body by 
means of receptors they bear on their surfaces. 
These receptors are made up of between five and 
eight components that can vary from one cell to an- 
other, so that one T cell can recognize poliovirus by 
means of its receptor, and another, measles. Usually 
a particular T cell must have the right combination 
of all five to eight components to recognize a par- 
ticular invader; for example, an individual who has 
not previously been exposed to measles will have 
few reactive T cells and respond poorly to the virus 
when first infected. There are some exceptions, 
however, to this rule. So-called superantigens stim- 
ulate all T cells bearing a particular version of one 
of the components, regardless of the others. 
Among these exceptions are a collection of toxins 
produced by Staphylococcus aureus that cause 
food poisoning or toxic shock in humans. Because 
they are superantigens, these toxins are able to 
stimulate a large number of T cells. The toxin that 
causes toxic shock, for example, will react with 
about 10% of all T cells in a given individual, or ap- 
proximately 100,000,000,000 cells. The laboratory 
of Investigator John W Kappler, Ph.D. (National 
Jewish Center for Immunology and Respiratory 
Medicine, Denver) has predicted that it is the stim- 
ulated T cells that cause all or most of the symp- 
toms arising from exposure to the staphylococcal 
toxins, rather than the toxins themselves. 
Research in the laboratory of Investigator Charles 
A. Janeway, Jr., M.D. (Yale University) seeks to char- 
acterize the cellular interactions and transmem- 
brane signaling events that lead to the selection of 
a self-tolerant and self MHC (major histocompati- 
bility complex) -restricted T cell antigen receptor 
(TCR) repertoire. The demonstration in this labora- 
tory that the TCR is oriented to the peptide-MHC 
ligand, that crosslinking and conformational 
change both contribute to T cell activation, and 
that self peptides are poorly represented in the 
thymic cortex has led Dr. Janeway to propose that 
either crosslinking or conformational change alone 
induced by TCR interactions with MHC molecules 
in the thymic cortex may generate a novel signal for 
positive selection of self MHC-recognizing T cells. 
These events are now being described in terms of 
signal transduction. 
The long-term goal of Assistant Investigator Jef- 
frey M. Leiden, M.D., Ph.D. (University of Michigan) 
and his colleagues is to understand the molecular 
mechanisms that regulate gene expression during 
cellular differentiation and activation. Their studies 
of the regulation of the TCR a-chain gene have 
identified the genetic elements and protein factors 
that are responsible for specifically turning on the 
expression of this gene in human T cells. The labo- 
ratory has cloned one of the protein factors that 
regulate the expression of the TCR a-chain gene, as 
well as a number of other cAMP-responsive genes. 
Dr. Leiden is also interested in cardiac troponin C, 
the calcium-binding protein that regulates the force 
of contraction in the heart. The laboratory recently 
cloned the cardiac troponin C gene, analyzed its ex- 
pression during muscle cell development, and pro- 
duced monoclonal antibodies specific for this pro- 
tein. These antibodies may be useful in the early 
diagnosis of patients with heart attacks. 
The activation of T lymphocytes after antigen 
challenge is a central feature of the immune re- 
sponse. The studies of Associate Investigator Arthur 
Weiss, M.D., Ph.D. (University of California at San 
Francisco) and his colleagues are an attempt to un- 
derstand how cell surface molecules, specifically 
the TCR, initiate T cell responses. Stimulation of 
Continued 
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