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ß+CD4+ Thymocytes Expressing L-Selectin Mediate "Active Tolerance" in the Nonobese Diabetic Mouse1
*
Institut National de la Santé et de la Recherche Médicale, Unité 25, and
Centre National de la Recherche Scientifique, Unité de Recherche Associée 1461, Hôpital Necker, Paris, France
Pathogenic autoreactive T lymphocytes are mediators of spontaneous
insulin-dependent diabetes in nonobese diabetic (NOD) mice. This is
demonstrated by their capacity to transfer diabetes into syngeneic
immunoincompetent recipients. In addition, especially in prediabetic
NOD mice, peripheral CD4+ T lymphocytes were identified
that are highly effective, in conventional mixing cotransfer
experiments, at preventing disease transfer. The present data
demonstrate that mature heat-stable
Ag-TCR
ß+CD8- thymocytes from
prediabetic NOD mice also express this inhibitory capacity. Selection
using an L-selectin (CD62L)-specific Ab showed that
TCRß+CD4+CD62L+ thymocytes,
emerging from the mainstream differentiation pathway, concentrate this
ability to regulate autoreactive effectors. Compared with mature
TCRß+CD8- thymocytes, significantly lower
numbers of TCRß+CD4+CD62L+
were sufficient to achieve an efficient inhibition of disease transfer
into NOD-scid recipients. This protective ability was
potentiated following in vitro culture in the presence of IL-7. In
contrast, TCRß+CD62L- thymocytes, highly
enriched in class I-restricted NK T cells, were unable to influence
diabetes transfer. Identical results were obtained using thymocytes
that have been cultured in vitro for 4 days in the presence of IL-7.
These results support the active role in NOD mice of a thymus-derived
CD4+ subset that controls peripheral pathogenic autoimmune
effectors.
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