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* Center for Comparative Medicine and
Department of Pathology, Microbiology and Immunology, University of California, Davis, CA 95616; and
Department of Epidemiology and Biostatistics, Center for Bioinformatics and Molecular Biostatistics, and
Department of Medicine and Program in Immunology, University of California, San Francisco, CA 94143
Induction of primary B cell responses requires the presence of Ag and costimulatory signals by T cells. Innate signals further enhance B cell activation. The precise nature and kinetics of such innate immune signals and their functional effects are unknown. This study demonstrates that influenza virus-induced type I IFN is the main innate stimulus affecting local B cells within 48 h of infection. It alters the transcriptional profile of B cells and selectively traps them in the regional lymph nodes, presumably via up-regulation of CD69. Somewhat paradoxically, innate B cell stimulation inhibited the ability of regional lymph node B cells to clonally expand following BCR-mediated stimulation. This inhibition was due to IFNR-signaling independent B cell intrinsic, as well as IFNR-dependent B cell extrinsic, regulation induced following influenza infection. IFNR-mediated signals also reduced B cell migration to various chemotactic agents. Consistent with the lack of responsiveness to CCR7 ligands, unaltered or reduced expression of MHC class II and genes associated with MHC class II Ag processing/presentation and CD40, B cells were unable to induce proliferation of naive CD4 T cells. Instead, they showed increased expression of a subset of nonclassical MHC molecules that facilitate interaction with 
T cells and NK T cells. We conclude that type I IFN is the main "third" B cell signal following influenza infection causing early trapping of B cells in regional lymph nodes and, at a time when cognate T cell help is rare, enhancing their propensity to interact with innate immune cells for noncognate stimulation.
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 a grant from the National Institutes of Health (NIH)/National Institute of Allergy and Infectious Diseases (AI51354 to N.B.) and was conducted in part in a facility constructed with support from Research Facilities Improvement Grant C06 RR-12088 from the NIH/National Center for Research Resources. F.C.R. was supported in part by the Deutsche Forschungsgemeinschaft (RA1373).
2 Address correspondence and reprint requests to Dr. Nicole Baumgarth, Center for Comparative Medicine, University of California, County Road 98 and Hutchison Drive, Davis, CA 95616. E-mail address: nbaumgarth{at}ucdavis.edu
3 Abbreviations used in this paper: MLN, mediastinal lymph node; PLN, peripheral lymph node; MHCII, MHC class II; MHCI, MHC class I; PI, propidium iodide; IFIT, IFN-induced proteins with tetratrico peptide repeat.
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