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*
Centre National de la Recherche Scientifique, Unité Mixte de Recherche 8603, Université René Descartes, Paris V, Hôpital Necker, Paris, France;
Institut National de la Santé et de la Recherche Médicale, Unité 25, and Association Claude Bernard, Hôpital Necker, Paris, France; and
Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Gunma, Japan
NKT cells are a versatile population whose immunoregulatory
functions are modulated by their microenvironment. We demonstrate
herein that in addition to their IFN-
production, NKT lymphocytes
stimulated with IL-12 plus IL-18 in vitro underwent activation in terms
of CD69 expression, blast transformation, and proliferation. Yet they
were unable to survive in culture because, once activated, they were
rapidly eliminated by apoptosis, even in the presence of their survival
factor IL-7. This process was preceded by up-regulation of Fas (CD95)
and Fas ligand expression in response to IL-12 plus IL-18 and was
blocked by zVAD, a large spectrum caspase inhibitor, as well as by
anti-Fas ligand mAb, suggesting the involvement of the Fas pathway.
In accordance with this idea, NKT cells from Fas-deficient
C57BL/6-lpr/lpr mice did not die in these conditions,
although they shared the same features of cell activation as their
wild-type counterpart. Activation-induced cell death occurred also
after TCR engagement in vivo, since NKT cells became apoptotic after
injection of their cognate ligand, 
-galactosylceramide, in
wild-type, but not in Fas-deficient, mice. Taken together, our data
provide the first evidence for a new Fas-dependent mechanism allowing
the elimination of TCR-dependent or -independent activated NKT cells,
which are potentially dangerous to the organism.
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