The T Cell Repertoire 
John W. Kappler, Ph.D. — Investigator 
Dr. Kappler 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 Microbiology 
and Immunology and of Medicine at the University of Colorado Health Sciences Center, Denver. 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 Rochester, 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. 
AS protection against invasion by foreign or- 
ganisms, higher animals have evolved a 
complex collection of cells and chemicals 
broadly termed the immune system. Components 
of this system are able to recognize foreign mate- 
rial in the body and give rise to a series of events 
that cause the destruction or inactivation of the 
invader. Cells arising in the thymus, the T lym- 
phocytes, are central to the efficient function of 
this system. 
T cells bear receptors on their surfaces that are 
able to interact specifically with foreign material. 
Such interaction stimulates these cells to pro- 
duce chemicals that allow other cells, and the T 
cells themselves, to respond to the invader. There 
are two kinds of T cells, bearing or 76 recep- 
tors respectively. The a/? receptors are made up 
of several segments — Va, Ja, VjS, D/3, and J(8 — 
each of which can differ in structure from one T 
cell to another. This is possible because the DNA 
of higher mammals contains a number of alter- 
nate genes for each of these segments. As each T 
cell develops, it selects a different combination 
of these genes, and therefore eventually ex- 
presses receptors that are not exactly the same 
in structure as those of its fellows. It is these varia- 
tions in a/3 receptor sequence that enable one T 
cell to recognize influenza virus, for example, 
and another poliovirus. 
In order for T cells to recognize most foreign 
materials, they must bear exactly the right combi- 
nation of variable segments — Va, Ja, etc. The 
proper combinations are usually rare, so when an 
animal is confronted with an invading organism, 
the cells that can actually recognize the invader 
are few, probably about one in 100,000 or one in 
a million of all T cells. This fact does not hold 
true, however, for special types of foreign mate- 
rial called superantigens. 
Superantigens bind to special cell-surface mol- 
ecules — class II proteins of the major histocom- 
patibility complex (MHC). They then interact 
with the VjS portion of the T cell receptor, almost 
without regard to the composition of its other 
variable elements. Since there are only about 75 
different sequences for V(8 in humans, any given 
superantigen will, theoretically, react with at 
least 1 percent of all T cells. In the mouse, with 
fewer different V/3 sequences, superantigens 
react with at least 5 percent of T cells. In fact, a 
particular superantigen can react in some cases 
with up to 30 percent of all T cells in either of 
these species. 
The fact that superantigens can react with so 
many T cells causes them to have some important 
pathogenic properties. For example, massive 
stimulation of T cells by superantigens causes 
toxic shock in humans, and there is reason to be- 
lieve that these antigens may be involved in cer- 
tain autoimmune diseases. 
Our laboratory has recently been studying the 
interaction among superantigens, the V/3 portions 
of T cell receptors, and the class 11 MHC proteins. 
A staphylococcal toxin, SEB, has been used as a 
model for these experiments. Amino acids have 
been identified in SEB that control the binding of 
this protein to V/8 or class II. 
In many cases proteins that must bind to two 
different target molecules express their binding 
sites in different domains. That is, the different 
functions of the protein are separated spatially. 
Surprisingly, this does not seem to be the case for 
SEB. The binding sites of this protein for V(8 and 
class II appear to be interwoven, as though they 
must lie in close proximity. 
The structural studies on SEB have led to the 
creation of a collection of mutant SEBs, some able 
to bind class II MHC but not V/3, some with a more 
limited range of V/3 specificities than SEB itself, 
and some able to bind neither MHC nor the T cell 
receptor. These mutant SEBs are now being 
screened as vaccines. Mice preimmunized with 
the mutant molecules are no longer sensitive to 
the toxic effects of SEB given later. 
Our laboratory and others have discovered a 
second class of superantigens, encoded by retrovi- 
ruses that cause mammary tumors in the mouse. 
Although the genes coding for these superanti- 
gens have been known for some time, the struc- 
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