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Regulates Natural Antibody Production, Marginal Zone and B-1 B Cell Function, and Autoantibody Responses1
*Department of Microbiology and Immunology, Infection, Inflammation, and Immunity (I3) and CELL Research Groups, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada;
Department of Medicine, University of California at San Diego, La Jolla, CA 92093;
Calistoga Pharmaceuticals Inc., Seattle, WA 98121; and
Centre for Cell Signalling, Institute of Cancer, Barts and London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom
B-1 and marginal zone (MZ) B cells produce natural Abs, make Ab responses to microbial pathogens, and contribute to autoimmunity. Although the 
isoform of the PI3K p110 catalytic subunit is essential for development of these innate-like B cells, its role in the localization, activation, and function of normal B-1 and MZ B cells is not known. Using IC87114, a highly selective inhibitor of p110 enzymatic activity, we show that p110 is important for murine B-1 and MZ B cells to respond to BCR clustering, the TLR ligands LPS and CpG DNA, and the chemoattractants CXCL13 and sphingosine 1-phosphate. In these innate-like B cells, p110 activity mediates BCR-, TLR- and chemoattractant-induced activation of the Akt prosurvival kinase, chemoattractant-induced migration, and TLR-induced proliferation. Moreover, we found that TLR-stimulated Ab responses by B-1 and MZ B cells, as well as the localization of MZ B cells in the spleen, depend on p110 activity. Finally, we show that the in vivo production of natural Abs requires p110 and that p110 inhibitors can reduce in vivo autoantibody responses. Thus, targeting p110 may be a novel approach for regulating innate-like B cells and for treating Ab-mediated autoimmune diseases.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This research was supported by Canadian Institutes of Health Research Grant (to M.R.G.), National Institutes of Health Grants R01 HL086559 and P01 HL088093 (to J.L.W.), and a grant from the Leducq Fondation (to J.L.W.). C.A.D. was funded by studentships from the Michael Smith Foundation for Health Research and the University of British Columbia. K.H. was supported by Scientist Development Grant 0630228N from the American Heart Association. StemCell Technologies (Vancouver, British Columbia, Canada) provided financial support for reagents.
2 K.H. and L.F. contributed equally to this work.
3 Current address: Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Gothenburg, Sweden.
4 Current address: ZymoGenetics Inc., Seattle, WA 98102.
5 K.D.P. and M.R.G. contributed equally to this work.
6 Address correspondence and reprint requests to Dr. Michael R. Gold, Department of Microbiology and Immunology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada. E-mail address: mgold{at}interchange.ubc.ca
7 Abbreviations used in this paper: MZ, marginal zone; KI, knock-in; LDL, low density lipoprotein; MAA, malondialdehyde-acetaldehyde; MDA, malondialdehyde; OxLDL, oxidized LDL; S1P, sphingosine 1-phosphate; SRBC, sheep RBC.
8 The online version of this article contains supplemental material.
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