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

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.

Activation of invariant natural killer T cells by α-galactosylceramide ameliorates myocardial ischemia/reperfusion injury in mice

“…Therefore, we could not directly demonstrate the source of IL-10 production. IL-10 has been shown to be produced by iNKT cells themselves on exogenous stimulation [51]. However, αGC-activated iNKT cells may stimulate other immune cells to produce IL-10.…”

Emerging concepts in CD8+ T regulatory cells

“…Within the spleen, CD-1d-reactive NKT cells produce RANTES, which recruits precursor CD8 + T regs and additional eye-derived F4/80 + APC to the spleen [23]. NKT cells produce IL-10, a crucial cytokine needed for the generation of ACAID CD8 + T regs [24]. NKT cells also produce urokinase-type plasminogen activator (uPA), which contributes to the generation of CD8 + T regs by binding to the uPA receptor on on F4/80 + APC within the spleen and converting latent TGF-β into its active form.…”

IFN‐γ‐producing NKT cells exacerbate sepsis by enhancing C5a generation via IL‐10‐mediated inhibition of CD55 expression on neutrophils

“…Upon TCR engagement in vivo, NKT cells rapidly secret large amounts of IL-4, IFN-γ, and IL-10, all of which play crucial roles in the regulation of immune responses [24,25]. To explore whether cytokine production by NKT cells regulates C5a generation in sepsis, we examined the patterns of IL-4, IFN-γ, and IL-10 expression in serum and PLF of WT and CD1d −/− mice.…”

“…Based on these findings, it is likely that the higher levels of C5a found in WT mice relative to CD1d −/− mice are attributable to indirect C5a generation by non-NKT cells rather than direct C5a production by NKT cells during CLP-induced sepsis. Upon TCR engagement in vivo, NKT cells rapidly secret large amounts of IL-4, IFN-γ, and IL-10, all of which play crucial roles in the regulation of immune responses [24,25]. To explore whether cytokine production by NKT cells regulates C5a generation in sepsis, we examined the patterns of IL-4, IFN-γ, and IL-10 expression in serum and PLF of WT and CD1d −/− mice.…”