NK T Cell-Derived IL-10 Is Essential for the Differentiation of Antigen-Specific T Regulatory Cells in Systemic Tolerance

TLDR

In the ACAID model of systemic tolerance, T regulatory cell differentiation occurs in the spleen and requires NK T cells. The authors examined cytokine profiles of heterogeneous and enriched splenic NK T cells to elucidate the mechanism of NK T cell–dependent Tr cell differentiation. NK T cell–derived IL‑10 is essential for generating antigen‑specific regulatory T cells and inducing systemic tolerance, as evidenced by the failure of Jα281‑knockout and IL‑10‑knockout mice to develop ACAID and the restoration of ACAID by wild‑type NK T cells.

Abstract

Abstract In a model of systemic tolerance called Anterior Chamber-Associated Immune Deviation (ACAID), the differentiation of the T regulatory (Tr) cells depends on NK T cells and occurs in the spleen. We now show that the CD1d-reactive NK T cell subpopulation, required for development of systemic tolerance, expresses the invariant Vα14Jα281 TCR because Jα281 knockout (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 mediating systemic tolerance was studied by defining the cytokine profiles in 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. )inoculated mice. However, IL-10 mRNA was not increased in spleens after i.v. inoculation. Finally, NK T cells from wild-type (WT) mice, but not from IL-10 KO mice, reconstituted the ACAID inducing ability in Jα281 KO mice. Thus, NK T cell-derived IL-10 is critical for the generation of the Ag-specific Tr cells and systemic tolerance induced to eye-inoculated Ags.