Antiviral immunity: Re-routing the interferon response through B cells

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Mouse cytomegalovirus infection induces expression of IFN alpha / beta via a lymphotoxin beta receptor (LT beta R)–NF- kappa B signaling pathway.

Immunologists typically think of the innate interferon- alpha / beta (IFN alpha / beta ) response to viruses as being mediated by plasmacytoid dendritic cells in a Toll-like receptor (TLR)-dependent manner. Now, Kirsten Schneider, Carl Ware, Chris Benedict and colleagues describe a new route to IFN alpha / beta production in response to mouse cytomegalovirus (MCMV) that involves B cells and is dependent on lymphotoxin (LT).


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The IFN alpha / beta response to MCMV infection in the spleen of C57BL/6 and BALB/c mice was shown to be biphasic, with a peak at 8 hours after infection followed by a second more sustained accumulation of IFN alpha / beta between 36 and 72 hours after infection. Mice deficient for both ligands of the LT beta receptor (Ltb^-/-Light^-/- mice) had a decrease in the level of mRNA encoding IFN beta in the spleen during the first peak of the IFN alpha / beta response to MCMV, but not by 48 hours after infection. The defective first phase of the IFN alpha / beta response to infection could be partially restored using an agonistic LT beta R-specific antibody. By contrast, mice deficient for both MyD88 and TRIF, which lack TLR signalling, had no defect in the early-phase IFN alpha / beta response to MCMV. So, the initial IFN alpha / beta response to MCMV in the spleen is LT beta R dependent but TLR independent.

The authors then carried out bone-marrow chimaera experiments to determine whether LT beta R expression by haematopoietic cells or radio-resistant stromal cells is required for IFN alpha / beta production in the spleen. LT beta R-deficient mice reconstituted with wild-type bone marrow, but not wild-type mice reconstituted with LT beta R-deficient bone marrow, had a defective early-phase IFN alpha / beta response. This indicates that stromal-cell expression of LT beta R is required to mount the initial IFN alpha / beta response to MCMV. Activation of the nuclear factor- kappa B (NF- kappa B) pathway by LT beta R requires NF- kappa B-inducing kinase (NIK); aly/aly mice (which have a functional mutation in NIK) infected with MCMV had a marked decrease in IFN alpha / beta production at 8 hours after infection. So, NF- kappa B signalling induced through LT beta R in stromal cells is required for the early IFN alpha / beta response to MCMV.

Naive B cells and CD4⁺ T cells in the spleen constitutively express LT on their surface and are therefore potential sources of the LT beta R ligand required for IFN alpha / beta induction. Mice that were deficient in B cells and, more specifically, mice that were conditionally deficient in LT beta in B cells (but not mice that were deficient in LT beta in T cells) had a defective early-phase IFN alpha / beta response to MCMV, which links naive B cells to innate immunity through the LT beta –LT beta R pathway.

The authors speculate that if dysregulated during persistent infection, this pathway might contribute to autoimmune diseases such as systemic lupus erythematosus, in which both B cells and IFN alpha / beta are known to have a role in pathogenesis.

Kirsty Minton

References

Schneider, K. et al. Lymphotoxin-mediated crosstalk between B cells and splenic stroma promotes the initial type I interferon response to cytomegalovirus. Cell Host Microbe 3, 67–76 (2008) | Article | PubMed |