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

Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA.
The Journal of Immunology (Impact Factor: 4.92). 11/2008; 181(7):4791-7. DOI: 10.4049/jimmunol.181.7.4791
Source: PubMed


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 alpha-C-GalCer, which induces a strong IFN-gamma but only a weak IL-4 production by iNKT cells, in contrast to the ligands alpha-GalCer (both IFN-gamma and IL-4) and OCH (primarily IL-4). The protective effect of alpha-C-GalCer was associated with a reduction of adaptive Ag-specific IFN-gamma and IL-17 production and was negated by systemic neutralization of IFN-gamma. These data suggest that pharmacological activation of iNKT cells protects from EAU at least in part by a mechanism involving innate production of IFN-gamma and a consequent dampening of the Th1 as well as the Th17 effector responses.

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    • "Transfer of WT NK cells 9 d after immunization, a time point before clinical disease onset but after the adaptive response has already developed, failed to affect disease (Fig. 2 G). This is in accord with our previous results, where only early, but not late, elicitation of IFN- could ameliorate disease (Tarrant et al., 1999; Grajewski et al., 2008), and suggests that IFN- from NK cells protects by inhibiting the priming, rather than the function, of adaptive effector T cells. "
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    ABSTRACT: IFN-γ is a pathogenic cytokine involved in inflammation. Paradoxically, its deficiency exacerbates experimental autoimmune encephalomyelitis, uveitis, and arthritis. Here, we demonstrate using IFN-γ(-/-) mice repleted with IFN-γ +/+: NK cells that innate production of IFN-γ from NK cells is necessary and sufficient to trigger an endogenous regulatory circuit that limits autoimmunity. After immunization, DCs recruited IFN-γ-producing NK cells to the draining lymph node and interacted with them in a CXCR3-dependent fashion. The interaction caused DCs to produce IL-27, which in turn enhanced IFN-γ production by NK cells, forming a self-amplifying positive feedback loop. IL-10, produced by the interacting cells themselves, was able to limit this process. The NK-DC-dependent IL-27 inhibited development of the adaptive pathogenic IL-17 response and induced IL-10-producing Tr1-like cells, which ameliorated disease in an IL-10-dependent manner. Our data reveal that an early NK-DC interaction controls the adaptive Th17 response and limits tissue-specific autoimmunity through an innate IFN-γ-IL-27 axis.
    Journal of Experimental Medicine 09/2015; DOI:10.1084/jem.20141678 · 12.52 Impact Factor
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    • "NKT cells may be particularly active in neuroinflammation, since the central nervous system (CNS) is enriched with glycolipids [22]. Furthermore, as the number of NKT cells is reduced in many autoimmune diseases, including multiple sclerosis, these cells were suggested to act as suppressors of autoimmune reactions [15], [23], [24]. However, their role in other neurodegenerative diseases with a local neuroinflammatory response remains unclear. "
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a rapidly progressing fatal neurodegenerative disorder characterized by the selective death of motor neurons (MN) in the spinal cord, and is associated with local neuroinflammation. Circulating CD4(+) T cells are required for controlling the local detrimental inflammation in neurodegenerative diseases, and for supporting neuronal survival, including that of MN. T-cell deficiency increases neuronal loss, while boosting T cell levels reduces it. Here, we show that in the mutant superoxide dismutase 1 G93A (mSOD1) mouse model of ALS, the levels of natural killer T (NKT) cells increased dramatically, and T-cell distribution was altered both in lymphoid organs and in the spinal cord relative to wild-type mice. The most significant elevation of NKT cells was observed in the liver, concomitant with organ atrophy. Hepatic expression levels of insulin-like growth factor (IGF)-1 decreased, while the expression of IGF binding protein (IGFBP)-1 was augmented by more than 20-fold in mSOD1 mice relative to wild-type animals. Moreover, hepatic lymphocytes of pre-symptomatic mSOD1 mice were found to secrete significantly higher levels of cytokines when stimulated with an NKT ligand, ex-vivo. Immunomodulation of NKT cells using an analogue of α-galactosyl ceramide (α-GalCer), in a specific regimen, diminished the number of these cells in the periphery, and induced recruitment of T cells into the affected spinal cord, leading to a modest but significant prolongation of life span of mSOD1 mice. These results identify NKT cells as potential players in ALS, and the liver as an additional site of major pathology in this disease, thereby emphasizing that ALS is not only a non-cell autonomous, but a non-tissue autonomous disease, as well. Moreover, the results suggest potential new therapeutic targets such as the liver for immunomodulatory intervention for modifying the disease, in addition to MN-based neuroprotection and systemic treatments aimed at reducing oxidative stress.
    PLoS ONE 08/2011; 6(8):e22374. DOI:10.1371/journal.pone.0022374 · 3.23 Impact Factor
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    • "These results indicate that, despite existence of mechanisms that can compensate for its absence, IL-17A has a proinflammatory and pathogenic role in the classical model of EAU induced by active immunization of retinal Ag in CFA. In addition to conventional effector CD4 + T cells, IL- 17A is also produced by CD8 + T cells (Peng and others 2007) and innate-like cells such as invariant NKT cells (Grajewski and others 2008) as well as gd T cells (Cui and others 2009). gd T cells are needed to develop full-blown EAU, but interestingly, treatment with recombinant IL-17 of animals immunized for EAU induction inhibited subsequent disease by suppressing IFN-g-producing effector T cells (Ke and others 2009). "
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    ABSTRACT: Autoimmune uveitis is a complex group of sight-threatening diseases that arise without a known infectious trigger. The disorder is often associated with immunological responses to retinal proteins. Experimental models of autoimmune uveitis targeting retinal proteins have led to a better understanding of the basic immunological mechanisms involved in the pathogenesis of uveitis and have provided a template for the development of novel therapies. The disease in humans is believed to be T cell-dependent, as clinical uveitis is ameliorated by T cell-targeting therapies. The roles of T helper 1 (Th1) and Th17 cells have been major topics of interest in the past decade. Studies in uveitis patients and experiments in animal models have revealed that Th1 and Th17 cells can both be pathogenic effectors, although, paradoxically, some cytokines produced by these subsets can also be protective, depending on when and where they are produced. The major proinflammatory as well as regulatory cytokines in uveitis, the therapeutic approaches, and benefits of targeting these cytokines will be discussed in this review.
    Journal of interferon & cytokine research: the official journal of the International Society for Interferon and Cytokine Research 07/2011; 31(10):733-44. DOI:10.1089/jir.2011.0042 · 2.00 Impact Factor
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