TLR signaling fine-tunes anti-influenza B cell responses without regulating effector T cell responses

Alex K. Heer, Abdijapar Shamshiev, Alena Donda, Satoshi Uematsu, Shizuo Akira, Manfred Kopf, Benjamin J. Marsland

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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 evototionarily 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-β, did not play a role in the development of CD+ 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-α, 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-α was critical for fine-inning 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.

Original languageEnglish
Pages (from-to)2182-2191
Number of pages10
JournalJournal of Immunology
Volume178
Issue number4
DOIs
Publication statusPublished - 15 Feb 2007
Externally publishedYes

Cite this

Heer, Alex K. ; Shamshiev, Abdijapar ; Donda, Alena ; Uematsu, Satoshi ; Akira, Shizuo ; Kopf, Manfred ; Marsland, Benjamin J. / TLR signaling fine-tunes anti-influenza B cell responses without regulating effector T cell responses. In: Journal of Immunology. 2007 ; Vol. 178, No. 4. pp. 2182-2191.
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TLR signaling fine-tunes anti-influenza B cell responses without regulating effector T cell responses. / Heer, Alex K.; Shamshiev, Abdijapar; Donda, Alena; Uematsu, Satoshi; Akira, Shizuo; Kopf, Manfred; Marsland, Benjamin J.

In: Journal of Immunology, Vol. 178, No. 4, 15.02.2007, p. 2182-2191.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - TLR signaling fine-tunes anti-influenza B cell responses without regulating effector T cell responses

AU - Heer, Alex K.

AU - Shamshiev, Abdijapar

AU - Donda, Alena

AU - Uematsu, Satoshi

AU - Akira, Shizuo

AU - Kopf, Manfred

AU - Marsland, Benjamin J.

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AB - 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 evototionarily 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-β, did not play a role in the development of CD+ 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-α, 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-α was critical for fine-inning 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.

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