The T Cell Repertoire 
John W. Kappler, Ph.D. — Investigator 
Dr. Kappler is also a member of the Department of Medicine of the National fewish Center for Immunology 
and Respiratory Medicine, Denver, and Professor of Microbiology and Immunology and of Medicine at 
the University of Colorado Health Sciences Center. He was educated at lehigh University and received his 
Ph.D. degree in biochemistry at Brandeis with Gordon Sato. He did postdoctoral work at the University 
of California, San Diego, with Richard Dutton. After holding faculty positions at the University of Roch- 
ester, he moved to his present position at the National Jewish Center. He was awarded the Wellcome 
Foundation Prize by the Royal Society and is a member of the National Academy of Sciences. 
HIGHER animals are at great risk of invasion 
by foreign organisms. In order to avert de- 
struction by parasites such as bacteria, they have 
developed complex protective mechanisms, 
broadly termed the immune system. The opera- 
tion of the system requires, first, that it recognize 
an invading organism and, second, that it mount 
an effective response to destroy the invader. 
Our laboratory is particularly interested in the 
first process, the means by w^hich the immune 
system recognizes foreign material. It does so pri- 
marily by use of lymphocytes (white blood cells) 
of three different types: B cells, and T cells bear- 
ing and 76 receptors. We have concentrated 
on ajS-bearing T cells. 
Mice contain about 200 million, and humans 
about 1 million million such cells. All of the a/3 
receptors on each cell are identical. From one 
cell to another, however, the a/3 receptors differ 
in amino acid sequence. This is because, as T 
cells develop, each one chooses different compo- 
nents from which to build its receptors. 
The a/3 receptors are made up of five variable 
components: Va, Ja, V(8, D/3, and J/3. The develop- 
ing T cell chooses for its receptors 1 Va from a 
selection of about 50. Likewise, it chooses 1 Ja 
from about 50 Ja's, 1 from about 50 V/3's, 1 D/3 
from 6 D/3's, and 1 J/3 from 1 3 J;8's. Because each 
developing cell chooses, by chance, a different 
combination of Va's, Ja's, etc., and because these 
components are joined together in slightly differ- 
ent ways by different T cells, the T cells in a given 
animal can express a very large number of differ- 
ent receptors, perhaps as many as 10'°. 
When an invading organism enters the body, 
fragments of the organism (antigens) appear on 
cell surfaces, linked to one or more of a collec- 
tion of self proteins, the products of the major 
histocompatibility complex (MHC). So pre- 
sented, the fragments can be bound by T cells 
bearing the right receptors. Usually a T cell has to 
have just the right combination of Va, Ja, V|8, D/3, 
and J/3 in order to bind the fragments of a particu- 
lar invader. Consequently, for many such organ- 
isms, only a few T cells — perhaps 1 in 100,000 
— can recognize that the organism has arrived in 
the body. These few T cells, however, are stimu- 
lated to divide by their interaction with the in- 
vader, so in a few days they give rise to many cells 
able to bind fragments from the organism. Fi- 
nally, T cells differentiate into cells able to de- 
stroy the invader or to stimulate other cells to 
do so. 
A few years ago we discovered a collection of 
foreign materials that we named superantigens. 
These materials bind to MHC proteins and stimu- 
late T cells, but unlike most antigens they will 
stimulate almost any T cell bearing a particular 
V/3. Staphylococcal enterotoxin B, for example, 
will stimulate mouse T cells bearing the V;S8's or 
V/37, or human T cells bearing V/33. Because there 
is a reasonably large percentage of T cells in mice 
bearing the V/38's and V)87, or in humans bearing 
V/33, these superantigens stimulate a very large 
percentage of T cells at once, perhaps as many as 
10 percent of all cells in a given individual. This 
gross T cell stimulation causes overactivation of 
the cells, massive release of T cell mediators, and 
consequent illness. 
A number of organisms make superantigens. 
Staphylococci and streptococci are among the 
bacteria that produce them. Superantigens are 
also made by mycoplasma and by mice them- 
selves. We have been studying how these super- 
antigens bind to MHC and to the V/3 components 
of the T cell receptors. Our data show that the 
superantigens made by mice, and by staphylo- 
cocci, bind to V/3 at an exposed face of the mole- 
cule well away from the part of the T cell recep- 
tor that is thought to bind to conventional 
antigens plus MHC. There are also some indica- 
tions that the staphylococcal toxins bind to some 
human MHC proteins better than others. Since 
human beings differ widely in the sequences of 
the MHC proteins they make, perhaps this is why 
some individuals get food poisoning when they 
eat staphylococcus-contaminated egg salad, for 
example, whereas others at the same picnic eat 
the same egg salad without getting sick. 
We have also been studying the structures on 
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