was previously suggested that ap T cells are gener- 
ated only from those cells that failed to rearrange 7 
or 8 genes productively. Dr. Tonegawa's laboratory 
tested this model by analyzing transgenic mice con- 
structed with productively rearranged TCR 7 and 8 
genes. Contrary to the prediction of the previously 
published model, neither the absolute number nor 
the proportion of aP T cells is significantly altered 
in the thymus and spleen of the transgenic mice. In 
these ap T cells the transgene 7 is repressed, as are 
the endogenously derived C^-associated 7 genes 
present in many ap T cells of normal (nontrans- 
genic) mice. 
The repression seems to be mediated by a C^-as- 
sociated "silencer" element active in aP T cells, 
because a C^-associated 7 gene with limited flank- 
ing sequences introduced into aP T cells, as op- 
posed to the coexisting endogenous 7 gene, is dere- 
pressed. Based on these results, Dr. Tonegawa and 
his colleagues argue that the failure to rearrange 
both 7 and 8 genes productively is not a require- 
ment for the generation of aP thymocytes. They 
propose that the putative machinery acting on the 
7 silencer is activated in a fraction of immature thy- 
mocytes and that it is from these cells that aP thy- 
mocytes are generated. The silencer model of T cell 
development is supported by another observation: 
in transgenic mice constructed with the silencerless 
7 and 8 genes, development of ap T cells is severely 
blocked. 
V Recognition of a Self Major Histocompatibility 
Complex TL Region Product by 78 TCR. 
To understand the function of 78 T cells it is es- 
sential to identify the ligand of the TCR. For this 
purpose Dr. Tonegawa's laboratory prepared 76 T 
hybridomas and used a growth inhibition assay to 
screen them for their specificity. This led to the 
identification of one hybridoma, KN6, specific to a 
product of the self major histocompatibility com- 
plex (MHC) TL region. The ligand appears to be 
present on thymocytes, splenocytes, peritoneal ex- 
PUBLICATIONS 
udate cells, and embryonal carcinoma cell line PCC3. 
From the PCC3 cell. Dr. Tonegawa's laboratory 
cloned an MHC class I gene; the nucleotide se- 
quence of this gene was different from that of any 
of the previously reported class I genes. This gene 
encodes the KN6 ligand, as demonstrated by the 
specific reactivity of L cell transfectants with the 
KN6 cells. 
VI. Possible Functions of 78 T Cells. 
Dr. Tonegawa's laboratory believes that the 
ligands of 78 TCR, like those of ap TCR, are made 
up of an antigen-derived peptide complexed with 
a restricting element. It is suspected that general- 
ly the restricting elements for the 78 T cells are 
MHC class I or MHC class I-like molecules, such 
as those mapped in the TL region, which are dis- 
tinct from those for CDS"*^ aP T cells. These class I 
molecules may have evolved to present a special 
set of antigens to the immune system, which might 
be explained by postulating a special intracellu- 
lar pathway of peptide loading and/or common 
structural features of the presented peptides. Re- 
cent experiments have shown the recognition of 
mycobacterial heat-shock-like proteins by some 78 
T cells; this suggests which set of proteins may 
be presented efficiently by the restricting elements 
for 78 T cells. It may be that 78 T cell sub- 
populations with diverse TCR are primarily directed 
to a variety of mycobacteria and parasitical proto- 
zoa known to produce constitutively distinct heat- 
shock-like proteins that are structurally related. 
The 78 T cell subpopulations with undiversified 
TCR then may recognize a host's own stress pro- 
tein, which may be induced in the epithelial cells 
by a variety of unfavorable stimuli, such as viral in- 
fections, toxic chemicals, radiation, heat shock, and 
malignancy. 
Dr. Tonegawa is also Professor of Biology at the 
Massachusetts Institute of Technology, Center for 
Cancer Research. 
Articles 
Bonneville, M., Ito, K., Krecko, E.G., Itohara, S., Kappes, D., Ishida, I., Kanagawa, O., Janeway C.A., Jr., Mur- 
phy, D.B., and Tonegawa, S. 1989. Recognition of a self major histocompatibility complex TL region prod- 
uct by 78 T-cell receptors. Proc Natl Acad Sci USA 86:5928-5932. 
Bonneville, M., Janeway, C.A., Jr. , Ito, K., Haser, W, Ishida, I. , Nakanishi, N., and Tonegawa, S. 1988. Intestinal 
intraepithelial lymphocytes are a distinct set of 78 T cells. Nature 336:479-481. 
Continued 
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