IntroductionThe immune system responds to invading pathogens by recognizing their antigenic structures, while remaining unresponsive to self antigens. This simplified model, however, is challenged by the understanding that autoreactivity is a common feature of healthy organisms and a part of peripheral tolerance mechanisms. To generate animal models for autoimmune diseases, susceptible species are often immunized with self antigens. However, not all immunogenic self antigens have the capacity to provoke a pathogenic autoimmune response, and some of them confer protection (1). A widely accepted animal model for human rheumatoid arthritis is collageninduced arthritis (CIA) in mice. CIA is induced by immunizing susceptible mouse strains with cartilage-derived triple helical type II collagen (CII). In mice expressing the MHC class II molecule H-2A q , the disease-mediating epitope is an immunodominant glycopeptide derived from position 260-270 of rat CII (2). In comparison with heterologous CII, mouse CII, although capable of inducing arthritis, provokes a much weaker immune response to the immunodominant epitope and induces a lower incidence of arthritis (3). However, mouse CII immunization induces a recall proliferative response toward multiple epitopes in addition to the MHC class II-restricted CII 260-270 peptide (4). The major epitopes share a common motif, with the strongest located at position 707-721 (mCII [707][708][709][710][711][712][713][714][715][716][717][718][719][720][721] ). By investigating the immune response to this epitope, surprisingly, we found that this peptide was not MHC I/II restricted, but was binding and presented by CD1d, a cluster of

The existence of T cells restricted for the MHC I-like molecule CD1 is well established, but the function of these cells is still obscure; one implication is that CD1-dependent T cells regulate autoimmunity. In this study, we investigate their role in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis, using CD1-deficient mice on a C57BL/6 background. We show that CD1−/− mice develop a clinically more severe and chronic EAE compared with CD1+/+ C57BL/6 mice, which was histopathologically confirmed with increased demyelination and CNS infiltration in CD1−/− mice. Autoantigen rechallenge in vitro revealed similar T cell proliferation in CD1+/+ and CD1−/− mice but an amplified cytokine response in CD1−/− mice as measured by both the Th1 cytokine IFN-γ and the Th2 cytokine IL-4. Investigation of cytokine production at the site of inflammation showed a CNS influx of TGF-β1-producing cells early in the disease in CD1+/+ mice, which was absent in the CD1−/− mice. Passive transfer of EAE using an autoreactive T cell line induced equivalent disease in both groups, which suggested additional requirements for activation of the CD1-dependent regulatory pathway(s). When immunized with CFA before T cell transfer, the CD1−/− mice again developed an augmented EAE compared with CD1+/+ mice. We suggest that CD1 exerts its function during CFA-mediated activation, regulating development of EAE both through enhancing TGF-β1 production and through limiting autoreactive T cell activation, but not necessarily via effects on the Th1/Th2 balance.

Invariant natural killer T (iNKT) cells serve as early rapid responders in the innate immune response to self-derived autoantigens and pathogen-derived danger signals and antigens. iNKT cells can serve both as helpers for effector B cells and negatively regulate autoreactive B cells. Specifically, iNKT cells drive B cell proliferation, class switch, and antibody production to induce primary antigen-specific immune responses. On the other hand, inflammasome-mediated activation drives accumulation of neutrophils, which license iNKT cells to negatively regulate autoreactive B cells via Fas ligand (FasL). This positions iNKT cells at an apex to support or inhibit B cell responses in inflammation. However, it is unknown which effector mechanism dominates in the face of cognate glycolipid activation during chronic inflammation, as might result from glycolipid vaccination or infection during chronic autoimmune disease. We stimulated iNKT cells by cognate glycolipid antigen α-galactosylceramide (αGalCer) and measured B cell activation during interleukin 18 (IL-18)-induced chronic inflammation. Moreover, glycolipid-activated iNKT cells increased the serum concentration of autoantibodies, frequency of germinal center (GC) B cells, and antigen-specific plasma cells induced during chronic IL-18–mediated inflammation, as compared with IL-18 alone. Further, activation of iNKT cells via cognate glycolipid during IL-18–mediated inflammation overrides the licensing function of neutrophils, instead inducing iNKT follicular helper (iNKTfh) cells that in turn promote autoimmunity. Thus, our data demonstrate that glycolipids which engage iNKT cells support antigen-specific B cell help during inflammasome-mediated inflammation.