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* Department of Immunology, Duke University Medical Center, Durham, NC 27710; and
Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo, Japan
Autoimmunity and inflammation are controlled in part by regulatory B cells, including a recently identified IL-10-competent CD1dhighCD5+ B cell subset termed B10 cells that represents 1–3% of adult mouse spleen B cells. In this study, pathways that influence B10 cell generation and IL-10 production were identified and compared with previously described regulatory B cells. IL-10-competent B cells were predominantly CD1dhighCD5+ in adult spleen and were the prevalent source of IL-10, but not other cytokines. B10 cell development and/or maturation in vivo required Ag receptor diversity and intact signaling pathways, but not T cells, gut-associated flora, or environmental pathogens. Spleen B10 cell frequencies were significantly expanded in aged mice and mice predisposed to autoimmunity, but were significantly decreased in mouse strains that are susceptible to exogenous autoantigen-induced autoimmunity. LPS, PMA, plus ionomycin stimulation in vitro for 5 h induced B10 cells to express cytoplasmic IL-10. However, prolonged LPS or CD40 stimulation (48 h) induced additional adult spleen CD1dhighCD5+ B cells to express IL-10 following PMA plus ionomycin stimulation. Prolonged LPS or CD40 stimulation of newborn spleen and adult blood or lymph node CD1dlow and/or CD5– B cells also induced cytoplasmic IL-10 competence in rare B cells, with CD40 ligation uniformly inducing CD5 expression. IL-10 secretion was induced by LPS signaling through MyD88-dependent pathways, but not following CD40 ligation. LPS stimulation also induced rapid B10 cell clonal expansion when compared with other spleen B cells. Thereby, both adaptive and innate signals regulate B10 cell development, maturation, CD5 expression, and competence for IL-10 production.
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1 This work was supported by National Institutes of Health Grants CA105001, CA96547, AI56363, and AI057157. J.-D.B. is supported by grants from Association pour la Recherche contre le Cancer, the Fondation René Touraine, and the Philippe Foundation.
2 K.Y., J.-D.B., and T.M. contributed equally to these studies and share first authorship.
3 Address correspondence and reprint requests to Dr. Thomas F. Tedder, Box 3010, Department of Immunology, Duke University Medical Center, Durham, NC 27710. E-mail address: thomas.tedder{at}duke.edu
4 Abbreviations used in this paper: CHS, contact hypersensitivity; CD40L/BTg, CD40L/B transgenic; CIA, collagen-induced arthritis; EAE, experimental autoimmune encephalomyelitis; hCD19Tg, human CD19 transgenic; int, intermediate; L+PIM, LPS, PMA, ionomycin, plus monensin; MZ, marginal zone; NZB/W, New Zealand Black/White.
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