Invariant NKT cells produce IL-17 through IL-23-dependent and -independent pathways with potential modulation of Th17 response in collagen-induced arthritis

Abstract

Abstract. Invariant natural killer T (iNKT) cells play a protective role in the development of certain autoimmune diseases. However, their precise role in the pathogenesis of autoimmune arthritis remains unclear. In this study, we examined the possible contribution of iNKT cells in collageninduced arthritis (CIA) by using iNKT cell-deficient mice (Jα281 -/-mice). CIA in these mice was markedly suppressed and interleukin (IL)-17 production was reduced in a native type II collagen (CII)-specific T cell response. Draining lymph nodes of CII-immunized Jα281 -/-mice contained a significantly low number of IL-17-producing T helper cells. To determine whether iNKT cells produce IL-17, we measured IL-17 by enzyme-linked immunosorbent assay in iNKT cells stimulated with the ligand, α-galactosylceramide (α-GalCer). Notably, splenocytes from Jα281 -/-mice stimulated in this way were negative for IL-17, whereas those from C57BL/6 mice produced IL-17. Immunostaining for IL-17 in iNKT cells confirmed intracellular staining of the protein.RT-PCR analysis showed that iNKT cells expressed retinoidrelated orphan receptor γT and IL-23 receptor. Moreover, cell sorting demonstrated that NK1.1 -iNKT cells were the main producers of IL-17 compared with NK1.1 + iNKT cells. IL-17 production by iNKT cells was induced by IL-23-dependent and -independent pathways, since iNKT produced IL-17 when stimulated with either IL-23 or α-GalCer alone. Our findings indicate that iNKT cells are producers and activators of IL-17 via IL-23-dependent and -independent pathways, suggesting that they are key cells in the pathogenesis of CIA through IL-17.

Activation of natural killer T cells by α-carba-GalCer (RCAI-56), a novel synthetic glycolipid ligand, suppresses murine collagen-induced arthritis

“…In animal models, NK T cells suppress the development and progression of diabetes mellitus [21], EAE [22] and systemic lupus erythematosus (SLE) [23]. However, NK T cells also act as effector cells in some murine models of RA by promoting Th17 responses, producing IL-17 and suppressing the production of transforming growth factor (TGF)-b [24][25][26][27][28]. These evidences suggest a dual function for NK T cells in autoimmunity.…”

Cytokine Profile of T Cells in the Joints of Rheumatoid Arthritis and Its Murine Models

“…On the other hand, alpha/beta T cells, especially Th17 cells, are essential for the induction of CIA because alpha/beta TCR deficient mice cannot mount CIA (Corthay, et al, 1999). In addition, IL-17-producing iNKT cells in CIA have been reported recently (Yoshiga, et al, 2008), but these cells were not analyzed in this study. The origin and functions of IL-17-producing gamma/delta T cells in physiological and pathological conditions have been elucidated recently.…”

Invariant Natural Killer T Cells in Rheumatoid Arthritis and Other Inflammatory Arthritides

“…This was subsequently demonstrated in experiments showing that the neutralisation of IFN-after day 10 postprimary immunisation results in IL-17 dependent exacerbation of CIA (Sarkar et al, 2009). Yoshiga et al (2008) confirmed the pathogenic role of iNKT cells in C57BL/6 CIA by noting the reduced disease incidence and severity in Jα281 knockout mice compared to wild-type mice. DLN cells from Jα281 -/ -mice stimulated with CII at day 11 post-primary immunisation produced similar amounts of IFN-and minimal IL-4, with increased IL-10 (not significantly) and significantly less IL-17.…”

“…Results showed that IL-17 is only produced by the NK1.1 -subset in response to α-GalCer and more weakly after IL-23 stimulation. Furthermore, α-GalCer-induced IL-17 could not be abrogated with IL-23 and IL-23 was not detectable in culture supernatant, suggesting that NK1.1 -iNKT cells can produce IL-17 is both IL-23-dependent and independent (Yoshiga et al, 2008).…”