Activation of Invariant NKT Cells Ameliorates Experimental Ocular Autoimmunity by A Mechanism Involving Innate IFN-γ Production and Dampening of the Adaptive Th1 and Th17 Responses

Abstract

Invariant NKT cells (iNKT cells) have been reported to play a role not only in innate immunity but also to regulate several models of autoimmunity. Furthermore, iNKT cells are necessary for the generation of the prototypic eye-related immune regulatory phenomenon, anterior chamber associated immune deviation (ACAID). In this study, we explore the role of iNKT cells in regulation of autoimmunity to retina, using a model of experimental autoimmune uveitis (EAU) in mice immunized with a uveitogenic regimen of the retinal Ag, interphotoreceptor retinoid-binding protein. Natural strain-specific variation in iNKT number or induced genetic deficiencies in iNKT did not alter baseline susceptibility to EAU. However, iNKT function seemed to correlate with susceptibility and its pharmacological enhancement in vivo by treatment with iNKT TCR ligands at the time of uveitogenic immunization reproducibly ameliorated disease scores. Use of different iNKT TCR ligands revealed dependence on the elicited cytokine profile. Surprisingly, superior protection against EAU was achieved with α-C-GalCer, which induces a strong IFN-γ but only a weak IL-4 production by iNKT cells, in contrast to the ligands α-GalCer (both IFN-γ and IL-4) and OCH (primarily IL-4). The protective effect of α-C-GalCer was associated with a reduction of adaptive Ag-specific IFN-γ and IL-17 production and was negated by systemic neutralization of IFN-γ. These data suggest that pharmacological activation of iNKT cells protects from EAU at least in part by a mechanism involving innate production of IFN-γ and a consequent dampening of the Th1 as well as the Th17 effector responses.

α-Galactosylceramide as a Therapeutic Agent for PulmonaryMycobacterium tuberculosisInfection

“…The ability of iNKT cells to produce IFN-g after a-GalCer stimulation is one of their most important features to mediate host protection and may have therapeutic implications (47,48). Given the importance of IFN-g in controlling Mtb growth and the fact that a-GalCer administration induces IFN-g production by iNKT cells and by NK cells after downstream activation (49), one explanation for how a-GalCer ameliorates pulmonary TB may simply be via the induction of IFN-g.…”

A look at autoimmunity and inflammation in the eye

“…Thus, NK and NKT cells may produce innate IFN-γ that is protective in EAU (58,59). Monocytic cells, in addition to functioning as inflammatory cells, can also differentiate to a regulatory phenotype, known as myeloid-derived suppressor cells, which inhibit autoaggressive T cells (60).…”

Autoimmunity in the immune privileged eye: pathogenic and regulatory T cells

“…As a consequence, its systemic production after in vivo administration of the NKT-specific ligand α-GalCer is low and cannot be detected in the serum. In contrast, IFN-γ is produced by NK1.1-positive as well as -negative NKT cells, in quantities easily detectable in serum after in vivo administration of α-GalCer [28,29].…”

“…Treatment of IRBP-CFA immunized mice with α-GalCer analogs that trigger different amounts of IFN-γ from NKT cells inhibits EAU, and the most protective analog is the one that causes highest production of IFN-γ [29]. The protected mice exhibit reduced adaptive IL-17 and IFN-γ responses to IRBP.…”