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* Centre for Rheumatology Research, Department of Medicine, University College London, United Kingdom;
Cancer Research United Kingdom, London, United Kingdom; and
Departments of Pediatrics and Immunology, Children’s Hospital and Regional Medical Center and University of Washington, Seattle, WA 98195
The immune system contains natural regulatory cells important in the maintenance of tolerance. Although this suppressive function is usually attributed to CD4 regulatory T cells, recent reports have revealed an immunoregulatory role for IL-10-producing B cells in the context of several autoimmune diseases including collagen-induced arthritis. In the present study, we attribute this suppressive function to a B cell subset expressing high levels of CD21, CD23, and IgM, previously identified as transitional 2-marginal zone precursor (T2-MZP) B cells. T2-MZP B cells are present in the spleens of naive mice and increase during the remission phase of arthritis. Following adoptive transfer to immunized DBA/1 mice, T2-MZP B cells significantly prevented new disease and ameliorated established disease. The suppressive effect on arthritis was paralleled by an inhibition of Ag-specific T cell activation and a reduction in cells exhibiting Th1-type functional responses. We also provide evidence that this regulatory subset mediates its suppression through the secretion of suppressive cytokines and not by cell-to-cell contact. The ability to regulate an established immune response by T2-MZP B cells endows this subset of B cells with a striking and previously unrecognized immunoregulatory potential.
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 work was supported by Wellcome Trust Grant 068629 (to C.M.) and National Institutes of Health Grant (CA81140 to D.J.R.). K.A.C.-R. is supported by the Instituto Mexicano Del Seguro Social. A.M.-B. was supported by the Elizabeth Campbell Endowment for Immunology Research.
2 Current address: Unidad de Investigacion Médica en Immunologia, Hospital de la Pediatría, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, México.
3 M.R.E. and C.M. contributed equally to this manuscript.
4 Address correspondence and reprint requests to Dr. Claudia Mauri or Dr. Michael R. Ehrenstein, Centre For Rheumatology Research, Department of Medicine, University College London, 46 Cleveland Street, London, U.K. E-mail addresses: c.mauri{at}ucl.ac.uk or m.ehrenstein{at}ucl.ac.uk
5 Abbreviations used in this paper: CIA, collagen-induced arthritis; CII, bovine collagen type II; DTH, delayed-type hypersensitivity; FO, follicular; int, intermediate; KO, knockout; MZ, marginal zone; MZP, MZ precursor; T1, transitional 1 (B cell); T2, transitional 2 (B cell); Treg, regulatory T cell.
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