Combined proinflammatory cytokine and cognate activation of invariant natural killer T cells enhances anti-DNA antibody responses

Saikiran K. Sedimbi, Thomas Hägglöf, Manasa G. Garimella, Shan Wang, Amanda Duhlin, Ana Coelho, Katrine Ingelshed, Emma Mondoc, Stephen G. Malin, Rikard Holmdahl, David P. Lane, Elizabeth A. Leadbetter, Mikael C.I. Karlsson

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)9054-9063
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number16
DOIs
StatePublished - Apr 21 2020

Keywords

  • Autoimmunity
  • B cells
  • Inflammation
  • NKT cells
  • Neutrophils

ASJC Scopus subject areas

  • General

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