Viral double-stranded RNA triggers Ig class switching by activating upper respiratory mucosa B cells through an innate TLR3 pathway involving BAFF.
Class switch DNA recombination (CSR) from IgM to IgG and IgA is crucial for antiviral immunity. Follicular B cells undergo CSR upon engagement of CD40 by CD40 ligand on CD4+ T cells. This T cell-dependent pathway requires 5-7 days, which is too much of a delay to block quickly replicating pathogens. To compensate for this limitation, extrafollicular B cells rapidly undergo CSR through a T cell-independent pathway that involves innate Ag receptors of the TLR family. We found that a subset of upper respiratory mucosa B cells expressed TLR3 and responded to viral dsRNA, a cognate TLR3 ligand. In the presence of dsRNA, mucosal B cells activated NF-kappaB, a transcription factor critical for CSR. Activation of NF-kappaB required TRIF (Toll/IL-1R domain-containing protein inducing IFN-beta), a canonical TLR3 adapter protein, and caused germline transcription of downstream CH genes as well as expression of AID (activation-induced cytidine deaminase), a DNA-editing enzyme essential for CSR. Subsequent IgG and IgA production was enhanced by BAFF (B cell-activating factor of the TNF family), an innate mediator released by TLR3-expressing mucosal dendritic cells. Indeed, these innate immune cells triggered IgG and IgA responses upon exposure to dsRNA. By showing active TLR3 signaling and ongoing CSR in upper respiratory mucosa B cells from patients with CD40 signaling defects, our findings indicate that viral dsRNA may initiate frontline IgG and IgA responses through an innate TLR3-dependent pathway involving BAFF.
Xu
Weifeng
W
Department of Pathology and Laboratory Medicine, Weill Graduate School of Medical Sciences, Cornell University, New York, NY 10021, USA.
Santini
Paul A
PA
Matthews
Allysia J
AJ
Chiu
April
A
Plebani
Alessandro
A
He
Bing
B
Chen
Kang
K
Cerutti
Andrea
A
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism; D053264:B-Cell Activating Factor / Q000378:metabolism*; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003564:Cytidine Deaminase / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000235:genetics / Q000276:immunology*; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D009092:Mucous Membrane / Q000166:cytology / Q000276:immunology; D012330:RNA, Double-Stranded / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D015854:Up-Regulation; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
D033942:Adaptor Proteins, Vesicular Transport; D053264:B-Cell Activating Factor; D019013:CD40 Antigens; D007136:Immunoglobulins; D012330:RNA, Double-Stranded; C470409:TICAM1 protein, human; C495344:TLR3 protein, human; D051196:Toll-Like Receptor 3; D000098830:AICDA (Activation-Induced Cytidine Deaminase); D003564:Cytidine Deaminase