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Howard Hughes Medical Institute and Section of Immunobiology, Yale University School of Medicine, New Haven, CT 06510
Whether intrathymic-positive and -negative selection of
conventional 
T cells occur in anatomically distinct sites is a
matter of debate. By using a system composed of two distinct immune
receptors, the Y-Ae mAb and the 1H3.1 (V1/V6) TCR,
both directed against the 52–68 fragment of the I-E-chain
(E52–68) bound to I-Ab, we examined the occurrence of
negative selection imposed in vivo by a self-peptide-self-MHC class II
complex with differential tissue expression. 1H3.1 TCR-transgenic (Tg)
mice were bred to mice having an I-E transgene with expression
directed to all MHC class II-positive cells, restricted to thymic
epithelial cells, or restricted to B cells, dendritic cells, and
medullary thymic epithelial cells. All 1H3.1 TCR/I-E double-Tg mice
revealed a severely diminished thymic cellularity. Their lymph node
cells were depleted of V6+CD4+ cells and
were unresponsive to E52–68 in vitro. The absolute number of
CD4+CD8+ thymocytes was drastically reduced in
all combinations, indicating that negative selection caused by an
endogenously expressed self-determinant can effectively occur in the
thymic cortex in vivo. Moreover, both cortical epithelial cells and,
interestingly, the few cortical dendritic cells were able to support
negative selection of CD4+CD8+ thymocytes,
albeit with a distinct efficiency. Collectively, these observations
support a model where, in addition to the avidity of the
thymocyte/stromal cell interaction, in vivo negative selection of
autoreactive TCR-Tg T cells is determined by accessibility to
self-peptide-self-MHC complexes regardless of the anatomical
site.
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