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* Department of Pathology and Laboratory Medicine,
Biochemistry, Cell and Molecular Biology Allied Program, and
Graduate Program of Immunology and Microbial Pathogenesis, Weill Graduate School of Medical Sciences of Cornell University, New York, NY 10021; and
Clinica Pediatrica e Istituto di Medicina Molecolare "A. Nocivelli," Universita' di Brescia, Brescia, Italy
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-
B, a transcription factor critical for CSR. Activation of NF-B required TRIF (Toll/IL-1R domain-containing protein inducing IFN-β), 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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants R01 AI057653, R01 AI057653-S1, R01 AI074378 (to A.C.), and T32 AI07621 (to W.X.), by an Irma T. Hirschl Scholar Award (to A.C.), by a Cancer Research Institute Fellowship (to P.S.), and by funds from Fondazione C. Golgi and Centro Immunodeficienze Mario Di Martino (to A.P.).
2 Address correspondence and reprint requests to Dr. Andrea Cerutti, Weill Medical College of Cornell University, Department of Pathology and Laboratory Medicine, 1300 York Avenue, Room C-410, New York, NY 10021. E-mail address: acerutti{at}med.cornell.edu
3 Abbreviations used in this paper: CD40L, CD40 ligand; 7-AAD, 7-amino-actinomycin; AID, activation-induced cytidine deaminase; APRIL, a proliferation-inducing ligand; BAFF, B cell activating factor of the TNF family; CpG DNA, DNA with deoxycytidylate-phosphate-deoxyguanylate motifs; CSR, class switch DNA recombination; DAPI, 4',6'-diamidine-2-phenylindole; DC, dendritic cell; DN, dominant negative; GC, germinal center; HIGM, hyper-IgM; I, intronic; Luc, luciferase; mDC, myeloid DC; NA, numerical aperture; pAb, polyclonal Ab; pDC, plasmacytoid DC; poly(I:C), polyinosinic/cytidylic acid; pTLR3, phosphorylated TLR3; QRT-PCR, quantitative real-time RT-PCR; S, switch; TACI, transmembrane activator, calcium modulator, and cyclophilin ligand interactor; TI, T cell independent; TRIF, Toll/IL-1R domain-containing protein inducing IFN-β.
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