Kh. Sonoda et al., NK T cell-derived IL-10 is essential for the differentiation of antigen-specific T regulatory cells in systemic tolerance, J IMMUNOL, 166(1), 2001, pp. 42-50
In a model of systemic tolerance called Anterior Chamber-Associated Immune
Deviation (ACAID), the differentiation of the T regulatory (Tr) cells depen
ds on NK T cells and occurs in the spleen. We now show that the CD1d-reacti
ve NK T cell subpopulation, required for development of systemic tolerance,
expresses the invariant V alpha 14J alpha 281 TCR because J alpha 281 knoc
kout (KO) mice were unable to generate Ag-specific Tr cells and ACAID, The
mechanism for NK T cell-dependent differentiation of Ag-specific Tr cells m
ediating systemic tolerance was studied by defining the cytokine profiles i
n heterogeneous and enriched NK T spleen cells. In contrast to there being
no differences in most regulatory cytokine mRNAs, both mRNA and protein for
IL-10 were increased in splenic NK T cells of anterior chamber (a.c.)-inoc
ulated mice. However, IL-10 mRNA was not increased in spleens after i.v. in
oculation. Finally, NK T cells from wild-type (WT) mice, but not from IL-10
KO mice, reconstituted the ACAID inducing ability in J alpha 281 KO mice.
Thus, NK T cell-derived IL-10 is critical for the generation of the Ag-spec
ific Tr cells and systemic tolerance induced to eye-inoculated Ags.