Combined proinflammatory cytokine and cognate activation of invariant natural killer T cells enhances anti-DNA antibody responses
| Autor: | 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 |
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| Rok vydání: | 2020 |
| Předmět: |
Inflammation
Male B-Lymphocytes B cells autoimmunity Interleukin-18 Galactosylceramides Mice Transgenic Biological Sciences Recombinant Proteins Disease Models Animal Mice NKT cells Immunology and Inflammation neutrophils Antibodies Antinuclear Chronic Disease Animals Humans Natural Killer T-Cells Female Injections Intraperitoneal |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 |
| Popis: | Significance iNKT cells can both provide help and inhibit B cell responses. Our data show that when iNKT cells are activated with the glycolipid agonist αGalCer together with the inflammatory cytokine IL-18, they switch from regulating autoreactive B cells to promoting their expansion. As a consequence, autoreactive B cell responses remain unchecked by iNKT cells. The glycolipid αGalCer has been shown to have promising effects when administered as an adjuvant to achieve a better response to vaccines, as an antitumor agent, as well as in the regulation of autoimmunity. Our results highlight a facet of αGalCer-mediated iNKT cell activation in the context of inflammation and have broad implications for understanding the regulation of autoimmunity and use of αGalCer in therapy. 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. |
| Databáze: | OpenAIRE |
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