the activation of the mature T cells could be totally 
blocked by the inhibitors. These results raise the 
intriguing possibility that the differential signaling 
apparatus used is stage-specific during thymocyte 
development. 
How Is T Cell Tolerance to Extrathymic 
Antigens Produced and Maintained? 
Clonal deletion appears to be the dominant mech- 
anism by which self-reactive thymocytes are ren- 
dered inoperative if the self antigens are present in 
the thymus. Since most self antigens are derived 
from extrathymic tissues, the mechanism by which 
self-tolerance to such antigens is generated is an im- 
portant one. To dissect this issue, Dr. Loh's group 
generated a transgenic mouse in which the MHC 
class I, L** molecule is targeted exclusively to the 
exocrine pancreas. This mouse was then mated to 
the 2CTCR transgenic mouse, whose receptor speci- 
ficity is against the L** molecule. 
Detailed analysis of the double-transgenic mice 
revealed no evidence of clonal deletion in the thy- 
mus. However, the peripheral T cells appeared to be 
anergic (unable to respond upon stimulation with 
the L'' molecule). Thus immunological tolerance 
appeared to be maintained, in this case, by the state 
of unresponsiveness rather than clonal deletion. Sur- 
prisingly, with the passage of time, the exocrine pan- 
creas appeared to be undergoing inflammation by 
infiltrating lymphocytes in the double-transgenic 
mice. 
These data strongly suggest that organ damage in 
the periphery may occur during the process of toler- 
ization if the self-reactive thymocytes are created in 
the thymus and allowed to exit. 
Dr. Loh is also Professor of Medicine, Genetics, 
and Molecular Microbiology at Washington Uni- 
versity School of Medicine and Assistant Physi- 
cian at Barnes Hospital, St. Louis. 
Books and Chapters of Books 
Loh, D.Y. 1992. The development of self-tolerance 
and MHC restriction. In Highlights in Allergy and 
Clinical Immunology (Wiithrich, B., Ed.). Seat- 
tle, WA: Hogrefe & Huber, pp 137-139. 
Articles 
Fields, L.E., and Loh, D.Y. 1992. Organ injury asso- 
ciated with extrathymic induction of immune tol- 
erance in doubly transgenic mice. Proc Natl Acad 
Sci USA 89:5730-5734. 
Lee, N.A., Loh, D.Y., and Lacy, E. 1992. CDS sur- 
face levels alter the fate of a/3 T cell receptor- 
expressing thymocytes in transgenic mice, f Exp 
Med 175:1013-1025. 
Loh, D.Y. 1991. Molecular requirements for cell 
fate determination during T-lymphocyte develop- 
ment. New Biol 3:924-932. 
Nakayama, K., and Loh, D.Y. 1992. No require- 
ment for p56''''' in the antigen-stimulated clonal 
deletion of thymocytes. Science 257:94-96. 
Robey, E.A., Ramsdell, P., Kioussis, D., Sha, W., 
Loh, D.Y., Axel, R., and Fowlkes, B.J. 1992. The 
level of CDS expression can determine the out- 
come of thymic selection. Cell 69:1089-1096. 
Six, A., Jouvin-Marche, E., Loh, D.Y., Cazenave, 
P.A., andMarche, P.N. 1991. Identification of a T 
cell receptor /3 chain variable region, V(S20, that is 
differentially expressed in various strains of mice. 
J Exp Med 174:1263-1266. 
CONTROL OF THE T CELL REPERTOIRE 
Philippa Marrack, Ph.D., Investigator 
In mice and humans the combinations of genetic 
elements, \a, V/3, Ja, and so on, that contribute to 
completed T cell receptors could create at least 10'° 
different ones. It is clear, however, that not all possi- 
ble receptors are expressed in any given individual. 
The factors behind this — self tolerance, positive se- 
lection, and the genetic elements themselves — 
have been investigated. 
Many T cells that could recognize self antigens die 
while developing in the thymus. The reasons for this 
are now being understood. Many antigens to self are 
expressed in the thymus, engaging the receptors on 
developing thymocytes with specificity for these an- 
tigens. Receptor ligation transduces signals — sig- 
nals that include an increase in Ca^^ concentration 
within the cell. Unlike mature T cells, immature T 
cells die if their cytoplasmic Ca^^ levels rise above a 
certain point. Thus antigens expressed in the thy- 
mus screen out potentially autoreactive cells. 
There are theoretical reasons to believe that not 
all self antigens reach the thymus. Recently Dr. 
Marrack showed this to be true. In collaboration 
IMMUNOLOGY 347 
