Paul A. Santini

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-κB, a transcription factor critical for CSR. Activation of NF-κB 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.

Cyclin-Dependent Kinase Directly Regulates Initiation of Meiotic Recombination

Meiosis is a specialized cell division that halves the genome complement, producing haploid gametes/spores from diploid cells. Proper separation of homologous chromosomes at the first meiotic division requires the production of physical connections (chiasmata) between homologs through recombinational exchange of chromosome arms after sister-chromatid cohesion is established but before chromosome segregation takes place. The events of meiotic prophase must thus occur in a strictly temporal order, but the molecular controls coordinating these events have not been well elucidated. Here, we demonstrate that the budding yeast cyclin-dependent kinase Cdc28 directly regulates the formation of the DNA double-strand breaks that initiate recombination by phosphorylating the Mer2/Rec107 protein and thereby modulating interactions of Mer2 with other proteins required for break formation. We propose that this function of Cdc28 helps to coordinate the events of meiotic prophase with each other and with progression through prophase.