The Role of T Cells in Health and Sickness 
Philippa Marrack, Ph.D. — Investigator 
Dr. Marrack is also a member of the Department of Medicine at the National Jewish Center for Immunol- 
ogy and Respiratory Medicine and Professor of Biochemistry, Biophysics and Genetics, of Microbiology 
and Immunology, and of Medicine at the University of Colorado Health Sciences Center, Denver. She was 
educated at the University of Cambridge, England, and took her Ph.D. in biological sciences at the MRC 
laboratory for Molecular Biology in Cambridge. She came to the United States to do postdoctoral work 
with Richard Dutton at the University of California, San Diego. From there she moved to the University 
of Rochester and then, after seven years, to her present position. Dr. Marrack was awarded the Wellcome 
Foundation Prize by the Royal Society and is a member of the National Academy of Sciences. 
T cells are absolutely essential to the health of 
higher vertebrates. They patrol the body, rec- 
ognize some invaders such as bacteria and vi- 
ruses, and orchestrate their destruction. The im- 
portance of these cells is tragically revealed by 
the devastating effects of AIDS, in which a certain 
type of T cell is inexorably destroyed. 
T cells recognize targets, using receptors on 
their surfaces. Each T cell has about 20,000 iden- 
tical receptors, and those on any given T cell 
differ from those on other T cells. Thus a human 
being has about a million million T cells, all bear- 
ing different receptors to help in defense. When 
an organism invades the body, a wide array of T 
cell receptors is available to bind to fragments of 
the organism, called antigens. By chance the re- 
ceptors on some of the T cells will be able to bind 
to these antigens. These T cells bearing bound 
receptors are stimulated to multiply and destroy. 
How does the body develop so many different T 
cell receptors? This is achieved by combining in 
the receptor one each of several elements for en- 
gagement. T cell receptors are made up of five 
variable elements: Va, Ja, V/?, D/S, and J/3. Each T 
cell picks for its receptor 1 Va out of about 50 
available Va's. Likewise the cell chooses 1 Ja 
from a collection of about 50 Ja's and 1 V/3 from 
about 50 V|8's. D/? and J|8 are chosen from pools of 
about 6 D|8's and 13 J|8's, respectively. By com- 
bining these different components in different 
ways, the total T cell pool manages to express 
many receptors and hence is able to bind many 
foreign organisms. 
One of the major theoretical problems in im- 
munology has always been the matter of toler- 
ance to self. If our T cells can recognize and de- 
stroy most foreign material — including, for 
example, skin grafts from some close relatives — 
how is it that our T cells do not attack and destroy 
M5? Recently we have shown that tolerance to self 
is created by at least two different means. The 
first involves T cell death. As T cells are develop- 
ing they go through a stage at which the binding 
of material to their receptors causes them to die. 
Developing T cells are almost bound to be ex- 
posed to self; therefore cells that are potentially 
self-reactive will die at this stage. At a later stage 
in the life history of T cells, another mechanism 
comes into play, and T cells that can react with 
self appear to be inactivated. 
We do not yet understand why T cells that can 
react with self are killed in some cases and inacti- 
vated in others. More importantly, perhaps, we 
do not understand why T cells that can react with 
self sometimes escape both these processes and 
emerge later to cause autoimmune diseases. 
There is good evidence, for example, that juve- 
nile diabetes occurs because T cells in some chil- 
dren are able to bind to material made by the 
pancreas. The T cells in question exercise this 
ability and destroy the pancreatic cells that se- 
crete insulin. 
In order to study this problem, we have re- 
cently started to work on T cells in humans, in 
collaboration with Brian Kotzin, a rheumatolo- 
gist at the National Jewish Center. Even though T 
cell receptors comprise five variable compo- 
nents, Va, VjS, etc., we found to our surprise that 
in mice we could understand a lot about T cell 
specificity, responses, and autoimmunity by 
studying just one part of the T cell receptor, V/?. 
For this reason we have begun our clinical studies 
by developing tools to explore V(8 use by T cells. 
At first we developed a molecular biological 
method — quantitative polymerase chain reac- 
tion — to measure what proportion of T cells in 
different individuals bore a particular V/?. Using 
this method, we showed that patients with toxic 
shock syndrome have very large numbers of T 
cells bearing V/32. This occurs because the bacte- 
ria that cause toxic shock, Staphylococcus au- 
reus, produce a toxin that stimulates human T 
cells bearing V(82 to divide. We believe, in fact, 
that the disease toxic shock is caused by massive 
replication of V(82-bearing cells and their 
copious secretion of lymphokines, hormone-like 
materials that are useful to the body in small 
quantities but which at high concentrations 
cause shock and death. 
299 
