TLR signaling fine-tunes anti-influenza B cell responses without regulating effector T cell responses.
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-beta, 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-alpha, 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-alpha 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.
Heer
Alex K
AK
Institute of Integrative Biology, Molecular Biomedicine, Swiss Federal Institute of Technology, Zürich-Schlieren, Switzerland.
Shamshiev
Abdijapar
A
Donda
Alena
A
Uematsu
Satoshi
S
Akira
Shizuo
S
Kopf
Manfred
M
Marsland
Benjamin J
BJ
D000818:Animals; D000914:Antibodies, Viral / Q000276:immunology; D000917:Antibody Formation / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000276:immunology; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology*; D016898:Interferon-alpha / Q000276:immunology; D016899:Interferon-beta / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D051196:Toll-Like Receptor 3 / Q000276:immunology*; D051199:Toll-Like Receptor 7 / Q000276:immunology*
D000914:Antibodies, Viral; D019013:CD40 Antigens; D007074:Immunoglobulin G; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C477038:Tlr7 protein, mouse; D051196:Toll-Like Receptor 3; D051199:Toll-Like Receptor 7; D023201:CD40 Ligand; D016899:Interferon-beta