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IL-21–induced B cell apoptosis mediated by natural killer T cells suppresses IgE responses

¹ Laboratory for Immune Regulation, ² Laboratory for Vaccine Design, ³ Laboratory for Cell Signaling, and ⁴ Laboratory for Immunogenomics, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan
⁵ Department of Molecular Immunology and ⁶ Otorhinolaryngology/Head and Neck Surgery, Chiba University School of Medicine, Chiba-City, Chiba 260-8670, Japan
⁷ Amgen Institute, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada
⁸ Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Suita Osaka 565-0871, Japan

CORRESPONDENCE Masaru Taniguchi: taniguti{at}rcai.riken.jp

Epidemiological studies have suggested that the recent increase in the incidence and severity of immunoglobulin (Ig)E-mediated allergic disorders is inversely correlated with Mycobacterium bovis bacillus Calmette Guerin (BCG) vaccination; however, the underlying mechanisms remain uncertain. Here, we demonstrate that natural killer T (NKT) cells in mice and humans play a crucial role in the BCG-induced suppression of IgE responses. BCG-activated murine V14 NKT cells, but not conventional CD4 T cells, selectively express high levels of interleukin (IL)-21, which preferentially induces apoptosis in B cells. Signaling from the IL-21 receptor increases the formation of a complex between Bcl-2 and the proapoptotic molecule Bcl-2–modifying factor, resulting in B cell apoptosis. Similarly, BCG vaccination induces IL-21 expression by human peripheral blood mononuclear cells (PBMCs) in a partially NKT cell–dependent fashion. BCG-activated PBMCs significantly reduce IgE production by human B cells. These findings provide new insight into the therapeutic effect of BCG in allergic diseases.

Abbreviations used: -GalCer, -galactosylceramide; BCG, Mycobacterium bovis bacillus Calmette Guerin; BM-DC, BM-derived DC; Bmf, Bcl-2–modifying factor; c, common -chain; IRAK, IL-1R– associated kinase; MNC, mononuclear cell; MyD88, myeloid differentiation factor 88; PGN, peptidoglycan; TLR, Toll-like receptor.

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