Development and Function of T Cells 
Susumu Tonegawa, Ph.D. — Investigator 
Dr. Tonegawa is also Professor of Biology at the Massachusetts Institute of Technology. He received a B.S. 
degree in chemistry from Kyoto University in Kyoto, Japan, and a Ph.D. degree in biology from the Uni- 
versity of California, San Diego. His postgraduate training and research were at UCSD in the laboratory 
of Masaki Hayashi and at the Salk Institute with Renato Dulbecco. Dr. Tonegawa was a member of the 
Basel Institute for Immunology in Basel, Switzerland, before Joining the Department of Biology and Center 
for Cancer Research at MIT. He was awarded the Nobel Prize for physiology or medicine in 1987. 
THE most critical step in the vertebrate im- 
mune response is the recognition of antigens 
by lymphocytes. This task is accomplished by two 
sets of glycoproteins: immunoglobulins (Igs) and 
T cell antigen receptors (TCRs). The most ex- 
traordinary feature of these proteins is their struc- 
tural variability, much of which originates from 
the ability of the encoding gene segments to un- 
dergo somatic rearrangement. 
All TCRs were initially thought to be composed 
of a heterodimeric protein composed of a- and 
j8-subunits. However, the search for the genes en- 
coding these polypeptides led to the identifica- 
tion of a third rearranging gene, 7, that was later 
shown to encode one of the two subunits of an- 
other heterodimeric, TCR 75. The characteristics 
of this new type of TCR and the development and 
function of the T lymphocytes that express it, 76 
T cells, have been the major focus of our research 
during the past several years. 
The two types of T cell — those expressing TCR 
76 and TCR afi — most certainly arise through two 
separate cell lineages that originate from a com- 
mon stem cell. The molecular mechanism where- 
with the two cell lineages segregate from the 
stem cell is of considerable interest, not only for 
immunologists but also for cellular biologists in 
general. Our previous studies suggested that 
there is a DNA element, called a silencer, asso- 
ciated with a 7 gene through which its expression 
is repressed in afi T lineage cells. Our data also 
suggested that the fate of a given precursor T cell 
is determined by whether or not it contains fac- 
tors that can specifically interact with the si- 
lencer element and thereby repress the asso- 
ciated 7 gene. 
We have now identified and characterized the 
silencer element — in fact, two elements, one lo- 
cated within and the other 3' to a 7 gene. Each of 
these elements alone can repress 7 gene tran- 
scription in an a/3 lineage cell but not in a yb 
lineage cell, and the two elements, where present 
in the same lineage cell, work synergistically. 
We have also identified a third DNA element be- 
tween the two silencer elements that enhances 7 
gene transcription, called an enhancer. We sus- 
pect that each of these transcriptional elements 
(silencers and enhancer) interacts with an array 
of factors, some of which are differentially pres- 
ent in ajS and 76 T cell lineages, and that the dif- 
ferential synthesis or activation of these factors is 
the key for the segregation of the two T cell 
lineages. 
One of the most intriguing features of 76 T cells 
is the compartmentalization of their subsets with 
different TCR repertoires to various epithelia. Us- 
ing transgenic mice that were produced by the 
microinjection of a pair of rearranged TCR 7 and 6 
genes into the pronuclei of fertilized eggs, we 
have shown that a given 76 T cell "homes" to a 
particular epithelium, being guided by a mecha- 
nism independent of the specificity of its 76 TCR. 
Furthermore, using mice whose thymuses had 
been surgically removed, we confirmed our ear- 
lier conclusion obtained with thymus-less 
"nude" mice: Development of 76 T cells that 
home to spleen and lymph nodes is thymus de- 
pendent, while that of 76 T cells associated with 
gut epithelium is not. 
Another intriguing feature of the compartmen- 
talized 75 T cells is that virtually no TCR diversity 
is present among the members of some of these 
subsets, namely the subset associated with epi- 
dermis (called skin-associated intraepithelial 
lymphocytes, or s-IEL) or the subset associated 
with the epithelial layer of vagina, uterus, and 
tongue (called vut-IEL). The structural homoge- 
neity of the 75 TCR in these tissues is all the more 
striking because their genes, like Ig and TCR a 
and (8 genes, have the capacity for diversity and 
because this capacity is indeed utilized in some 
other parts of the body, such as spleen and lymph 
nodes. 
By culturing fetal thymus outside the body in 
the presence of a monoclonal antibody that will 
specifically bind to 76 TCR, we have now demon- 
strated that the remarkable homogeneity of 76 
TCR of s-IEL and vut-IEL is a result of the strong 
selection of T cell clones expressing the particu- 
lar 76 TCRs through their interaction with un- 
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