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TLR Signaling Fine-Tunes Anti-Influenza B Cell Responses without Regulating Effector T Cell Responses¹

Alex K. Heer^*, Abdijapar Shamshiev^*, Alena Donda, Satoshi Uematsu, Shizuo Akira, Manfred Kopf^2,3,* and Benjamin J. Marsland^2,3,*

^* Institute of Integrative Biology, Molecular Biomedicine, Swiss Federal Institute of Technology, Zürich-Schlieren, Switzerland; Institute of Biochemistry, Epalinges, Switzerland; and Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan

Influenza is a ssRNA virus that has been responsible for widespread morbidity and mortality; however, the innate immunological mechanisms that drive the adaptive anti-influenza immune response in vivo are yet to be fully elucidated. TLRs are pattern recognition receptors that bind evolutionarily conserved pathogen-associated molecular patterns, induce dendritic cell maturation, and consequently aid the development of effective immune responses. We have examined the role of TLRs in driving effective T and B cell responses against influenza virus. We found TLR3 and its associated adapter molecule, Toll/IL-R domain-containing adaptor-inducing IFN-, did not play a role in the development of CD4⁺ or CD8⁺ T cell responses against influenza virus, nor did they influence influenza-specific B cell responses. Surprisingly, TLR7 and MyD88 also played negligible roles in T cell activation and effector function upon infection with influenza virus; however, their signaling was critical for regulating anti-influenza B cell Ab isotype switching. The induction of appropriate anti-influenza humoral responses involved stimulation of TLRs on B cells directly and TLR-induced production of IFN-, which acted to reduce IgG1 and increase IgG2a/c class switching. Notably, direct TLR signaling on B cells or T cell help through the CD40-CD40L interaction was sufficient to support B cell proliferation and IgG1 production, whereas IFN- was critical for fine-tuning the nature of the isotype switch. Taken together, these data reveal that TLR signaling is not required for anti-influenza T cell responses, but through both direct and indirect means orchestrates appropriate anti-influenza 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 has been supported by Grant 3100A0-100233/1 from the Swiss National Foundation.

² M.K. and B.J.M. contributed equally to this study.

³ Address correspondence and reprint requests to Dr. Benjamin J. Marsland, Institute of Integrative Biology, Molecular Biomedicine, Swiss Federal Institute of Technology, Wagistrasse 27, CH8952 Zurich-Schlieren, Switzerland; E-mail address: marsland{at}env.ethz.ch or Dr. Manfred Kopf, Institute of Integrative Biology, Molecular Biomedicine, Swiss Federal Institute of Technology, Wagistrasse 27, CH8952 Zurich-Schlieren, Switzerland; E-mail address: kopf{at}env.ethz.ch

⁴ Abbreviations used in this paper: TRIF, Toll/IL-R domain-containing adaptor-inducing IFN-; BAL, bronchoalveolar lavage; DC, dendritic cell; MDA5, melanoma differentiation-associated gene 5; RIG-I, retinoic acid-inducible protein 1; RT, room temperature.

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