Lymphotoxin-mediated crosstalk between B cells and splenic stroma promotes the initial type I interferon response to cytomegalovirus

Toll-like receptor (TLR)-dependent pathways control the production of IFN alpha beta, a key cytokine in innate immune control of viruses including mouse cytomegalovirus; (MCMV). The lymphotoxin (LT) alpha beta-LT beta receptor signaling pathway is also critical for defense against MCMV and thought to aid in the IFN beta response. We find that upon MCMV infection, mice deficient for lymphotoxin (LT)alpha beta signaling cannot mount the initial part of a biphasic IFN alpha beta response, but show normal levels of IFN alpha beta during the sustained phase of infection. Significantly, the LT alpha beta-dependent, IFN alpha beta response is independent of TLR signaling. B, but not T, cells expressing LT beta are essential for promoting the initial IFN alpha beta response. LT beta R expression is required strictly in splenic stromal cells for initial IFN alpha beta production to MCMV and is dependent upon the NF-kappa B-inducing kinase (NIK). These results reveal a TLR-independent innate host defense strategy directed by B cells in communication with stromal cells via the LT alpha beta cytokine system.