Details

Autor(en) / Beteiligte

• Xu, Weifeng
• Santini, Paul A
• Matthews, Allysia J
• Chiu, April
• Plebani, Alessandro
• He, Bing
• Chen, Kang
• Cerutti, Andrea

Titel

Viral Double-Stranded RNA Triggers Ig Class Switching by Activating Upper Respiratory Mucosa B Cells through an Innate TLR3 Pathway Involving BAFF

Ist Teil von

• The Journal of immunology (1950), 2008-07, Vol.181 (1), p.276-287

Ort / Verlag

United States: Am Assoc Immnol

Erscheinungsjahr

2008

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.