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Murine B Cell Response to TLR7 Ligands Depends on an IFN-β Feedback Loop¹

Nathaniel M. Green^2,*, Amy Laws^2,*, Kerstin Kiefer^*, Liliana Busconi^*, You-Me Kim, Melanie M. Brinkmann, Erin Hodges Trail^*, Kei Yasuda, Sean R. Christensen^¶, Mark J. Shlomchik^¶, Stefanie Vogel^||, John H. Connor^*, Hidde Ploegh, Dan Eilat^#, Ian R. Rifkin, Jean Maguire van Seventer and Ann Marshak-Rothstein^3,*

^* Department of Microbiology and Department of Medicine, Boston University School of Medicine, Boston, MA 02118; Whitehead Institute of Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA 02115; Department of Environmental Health, Boston University School of Public Health, Boston, MA 02118; ^¶ Section of Immunology, Yale University School of Medicine, New Haven, CT 06520; ^|| University of Maryland, Baltimore, MD 21201; and ^# Division of Medicine, Hadassah University Hospital, Jerusalem, Israel

Type I IFNs play an important, yet poorly characterized, role in systemic lupus erythematosus. To better understand the interplay between type I IFNs and the activation of autoreactive B cells, we evaluated the effect of type I IFN receptor (IFNAR) deficiency in murine B cell responses to common TLR ligands. In comparison to wild-type B cells, TLR7-stimulated IFNAR^–/– B cells proliferated significantly less well and did not up-regulate costimulatory molecules. By contrast, IFNAR1^–/– B cells did not produce cytokines, but did proliferate and up-regulate activation markers in response to other TLR ligands. These defects were not due to a difference in the distribution of B cell populations or a failure to produce a soluble factor other than a type I IFN. Instead, the compromised response pattern reflected the disruption of an IFN-β feedback loop and constitutively low expression of TLR7 in the IFNAR1^–/– B cells. These results highlight subtle differences in the IFN dependence of TLR7 responses compared with other TLR-mediated B cell responses.

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 grants from the Alliance for Lupus Research and National Institutes of Health (Grants AR50256 and AR35230 to A.M.R. and AI18797 to S.V.).

² N.M.G. and A.L. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Ann Marshak-Rothstein, Department of Microbiology, Boston University School of Medicine, 72 East Concord Street, Boston, MA 02118. E-mail address: amrothst{at}bu.edu

⁴ Abbreviations used in this paper: SLE, systemic lupus erythematosus; IFNAR, IFN-β receptor; WT, wild type; pDC, plasmacytoid dendritic cell; DC, dendritic cell; ODN, oligodeoxynucleotide; MZ, marginal zone; IRF, IFN regulatory factor; FO, follicular; IC, immune complex.