Activation of Invariant NKT Cells Ameliorates Experimental Autoimmune Uveitis (EAU)

Abstract

Purpose: : Invariant Natural Killer T cells (iNKT cells) that have a conserved T cell receptor and recognize glycolipid ligands presented by the CD1d molecule, have been reported to play a role in innate immunity and to exert regulatory functions in various models of autoimmunity. In this study we examine whether this applies to murine experimental autoimmune uveitis (EAU), a model for human autoimmune uveitis.

Methods: : Mice were immunized with IRBP in complete Freund’s adjuvant (CFA) with or without one of the iNKT cell activating ligands α–GalCer, α–C–GalCer or OCH. EAU scores were examined. In some experiments IFN–γ in treated mice was neutralized by infusion of anti–IFN–γ antibody (clone R4–6A2).

Results: : Activation of iNKT cells ameliorated EAU. Surprisingly, superior protection against EAU in C57BL/6 mice was achieved with α–C–GalCer, that induces a strong IFN–γ, but only a weak IL–4 response by iNKT cells. Conversely, neutralization of IFN–γ reversed the protective effect. α–GalCer (inducing both IFN–γ and IL–4) and OCH (inducing primarily IL–4) had a significantly weaker protective effect. In contrast, EAU scores of CD1d^–/– mice that (lack all NKT cells), as well as scores of Jα18–knockout mice (that lack invariant NKT cells) were comparable to WT mice.

Conclusions: : Deficient or lacking iNKT function by itself did not alter the course of EAU, suggesting that iNKT cells do not determine the threshold of EAU susceptibility. Importantly, however, pharmacological enhancement of iNKT function by treatment with synthetic CD1d ligands could be exploited to ameliorate disease. The magnitude and type of cytokine response triggered by the different iNKT ligands seems to affect protection. iNKT production of IFN–γ appears to account at least in part for the protective effects of NKT cells in EAU.

Keywords: autoimmune disease • uveitis-clinical/animal model • immunomodulation/immunoregulation