The Role of T Cells in Health and Sickness 
Philippa Marrack, Ph.D. — Investigator 
Dr. Marrack is also a member of the Division of Basic Immunology of the Department of Medicine at the 
National Jewish Center for Immunology and Respiratory Medicine, Denver, and Professor of Biochemistry, 
Biophysics and Genetics, of Microbiology and Immunology, and of Medicine at the University of Colorado 
Health Sciences Center, Denver. She took her Ph.D. in biological sciences at the MRC Laboratory for 
Molecular Biology in Cambridge, England, and then did postdoctoral work with Richard Dutton at the 
University of California, San Diego. From there she moved to the University of Rochester, and, after seven 
years, to her present position. Dr. Marrack is a member of the National Academy of Sciences and was 
recently awarded the Christopher Columbus Discovery Award for Biomedical Science. 
T cells are essential to the ability of higher ver- 
tebrates to resist disease. These cells are not 
only able to destroy invading organisms by killing 
cells in which such organisms live, but they also 
produce hormone-like substances that contribute 
to protection against invasion, by stimulating pro- 
duction of protective antibodies, for example. 
T cells bear receptors for antigen on their sur- 
face. There are about 20,000 receptors on each 
cell. These are composed of tw^o polypeptide 
chains, ol and (8, each made up of a number of 
variable elements: Va, Ja, V/3, D/?, andJjS. In each 
T cell the receptors are composed of different 
combinations of these elements, so that each T 
cell has receptors with a somewhat different 
structure. 
As far as we know, receptors are assembled ran- 
domly from the available Vas, Jas, and so on, 
while T cells are developing. Consequently there 
is a distinct possibility that some T cells will bear 
receptors able to interact with self antigens, i.e., 
components of the individual containing the T 
cells. These cells are a potential threat, since they 
could attack and destroy their own host. Usually, 
however, they themselves are destroyed or inacti- 
vated before they become mature enough to 
cause damage. 
There is reason to believe that some potentially 
self-reactive T cells avoid the processes of toler- 
ance and are allowed to mature. Even though they 
could attack tissues of their host, they seem not 
to, perhaps because the self antigens with which 
they could interact are sequestered in a tissue 
that they cannot reach. Occasionally, however, 
these self-reactive cells are activated by en- 
counter with an environmental antigen. After 
stimulation the cells become more motile and ac- 
tive and are then able to interact with and destroy 
the tissues of their host, causing a so-called au- 
toimmune disease. 
A number of human diseases — juvenile dia- 
betes, lupus erythematosus, and multiple sclero- 
sis among others — may be due to T cell malfunc- 
tion similar to that described above. Our own 
work, in collaboration with Brian Kotzin (Depart- 
ment of Pediatrics, National Jewish Center), has 
concentrated on rheumatoid arthritis. About 2 
million people in the United States suffer from 
this disease, which seems to be due to an immune 
attack on material in joints. We have shown that 
many of those afflicted have unexpectedly low 
levels of T cells bearing V|8 1 4 in their blood, and 
some of the missing cells are present in the fluid 
bathing the rheumatic joints. 
We have suggested that rheumatoid arthritis in- 
volves chronic invasion of the host by a foreign 
antigen able to interact with T cells bearing 
V/314. This antigen would first stimulate target T 
cells, and then cause their disappearance, proba- 
bly by the processes of tolerance described 
above. Perhaps the subset of V(8 14 -bearing cells 
that can recognize self antigens is waylaid and 
rescued from death by sequestration in the joints. 
Here they cause inflammation and the symptoms 
of arthritis. 
At the moment all these are simply ideas upon 
which to base future experiments on the cause, 
treatment, and prevention of rheumatoid arthri- 
tis. Meanwhile, we have begun a search for the 
foreign antigen that may interact with V|8l4- 
bearing T cells and thus start the disease. There is 
every indication that this is a superantigen, a spe- 
cial kind of antigen that interacts with T cells, 
primarily via the VjS portion of their receptors. It 
is also likely, as mentioned above, that the anti- 
gen is produced by a chronic infectious agent, 
such as a chronic virus. 
Until recently the only infectious agents 
known to produce superantigens were myco- 
plasma and bacteria, such as staphylococci and 
streptococci. These agents do not usually infect 
their hosts in a chronic fashion. Early in 1991, 
however, we and several other groups showed 
that certain viruses, a collection of retroviruses 
present in mice, can also express superantigens. 
Encouraged by this result, we decided to screen 
human viruses for such expression. Our prelimi- 
nary results suggest that Epstein-Barr virus, the 
273 
