Exogenous glycolipid agonists alter the inherent B cell regulatory function of iNKT cells in inflammatory milieu — ASN Events
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Exogenous glycolipid agonists alter the inherent B cell regulatory function of iNKT cells in inflammatory milieu (#27)

Sai Kiran Sedimbi 1 , Thomas Hägglöf 1 , Michael B Brenner 2 , Elizabeth A Leadbetter 3 , Mikael C I Karlsson 1
  1. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
  2. Department of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, U. S. A.
  3. Trudeau Institute, Saranac Lake, New York, U. S. A.

The inflammatory cytokine IL-18 induces self-reactive antibody responses that are regulated by invariant natural killer T (iNKT) cells at a pre germinal center (GC) check-point to prevent the formation of class switched, mature anti-self antibodies1 in a CD1d and neutrophil dependent manner. The potent glycolipid α-galactosylceramide (αGalCer) has been shown to both prevent (SLE, RA, T1D) and exacerbate (atherosclerosis, asthma) inflammatory diseases. However, it is not known whether αGalCer can alter the inherent regulatory role of iNKT cells. We employed an IL-18 model to address this question. Mice immunized with IL-18 for ten consecutive days received one injection of αGalCer, GSL-1, OCH or vehicle on day 1. Mice immunized with IL-18 + αGalCer, but not GSL-1 or OCH, had earlier, significantly higher, IgE titers compared to IL-18 alone. This increase was associated with higher levels of B-cell activating factor (BAFF) and neutrophil influx in the spleen. Interestingly, infiltrating neutrophils in IL-18 + αGalCer group had strikingly reduced CD1d expression as did marginal zone (MZ) B cells, compared to IL-18 alone. Concurrently, we observed an increase in GC B cells but not plasma cells in IL-18 + αGalCer group. Further, we found an increase in iNKT follicular helper (iNKTfh) cells, in IL-18+αGalCer and αGalCer groups compared to IL-18 group. The increase in GC B cells coincided with higher titers of anti-DNA IgG, IgG3 and IgM antibodies in mice immunized with IL-18 + αGalCer compared to those immunized with IL-18 or αGalCer . Consistent with their regulatory role, iNKT2 cells (PLZF+, RORγt-) constituted the majority of iNKT cells in mice immunized with IL-18 but not in those immunized with IL-18 + αGalCer. Based on these findings we conclude that in an IL-18 induced inflammatory milieu, αGalCer alters the inherent, B cell regulatory function of iNKT cells potentially resulting in detrimental anti-self responses.

  1. Enoksson SL, Grasset EK, Hagglof T, Mattsson N, Kaiser Y, Gabrielsson S, McGaha TL, Scheynius A, Karlsson MC (2011) The inflammatory cytokine IL-18 induces self-reactive innate antibody responses regulated by natural killer T cells. Proc Natl Acad Sci USA 108:E1399–E1407