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

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 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-β, 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-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-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.

Distinctive TLR7 Signaling, Type I IFN Production, and Attenuated Innate and Adaptive Immune Responses to Yellow Fever Virus in a Primate Reservoir Host

“…More recent support documenting the impact of depressed pDC number or function on the induction and maintenance of CD8 + T cell numbers and function have been obtained from studies of YF-17D infection in rapamycin-treated mice (which results in inhibition of IRF-7-dependent IFN-a production) and VSV-infected mice that had been conditionally depleted of pDCs (30,55). Although less is known about the role of TLRs, DCs, and IFN-a in the generation of long-lived memory B cell responses (56), IFN-a has been shown to enhance primary Ab responses, promote isotype switching, influence relative polarization of the Ab isotype profile, and, together with IL-6, stimulate plasma cell differentiation in mice (57)(58)(59)(60). However, detailed mechanistic studies to better understand the role and mechanisms of potentially important effects of TLR7/9 signaling and IFN-a production on the levels, isotype composition, generation of CD4 + T cell and B cell memory, and in the overall persistence of Ab production following specific infections and immunizations in both humans and nonhuman primates (as well as in other vertebrate species that represent natural hosts for zoonotic infections) are clearly needed.…”

Differential Role of TLR- and RLR-Signaling in the Immune Responses to Influenza A Virus Infection and Vaccination

“…Nevertheless, such cell-type specific innate immune recognition of influenza A virus through distinct signaling pathways has not been elucidated in vivo especially in the case of airway infection and vaccination. Furthermore, innate immunity control of the adaptive immune response by TLR-or RIG-like receptor (RLR)-dependent signaling pathways has not been clarified, whereas TLR-dependent (21) and -independent (22) adaptive immune responses to influenza A virus have been observed.…”

IDO Mediates TLR9-Driven Protection from Experimental Autoimmune Diabetes

“…Mice homozygous for the TLR3 (Tlr3 Ϫ/Ϫ ) and TLR9 (Tlr9 Ϫ/Ϫ ) targeted mutation raised on the C57BL/6 background were generated as described (17,18), and bred at the breeding facilities of the University of Perugia. Female NOD/Mrk mice, 4 wk of age, were purchased from Taconic Farms.…”