IL-17A Promotes Pulmonary B-1a Cell Differentiation via Induction of Blimp-1 Expression during Influenza Virus Infection

Abstract

B-1 cells play a critical role in early protection during influenza infections by producing natural IgM antibodies. However, the underlying mechanisms involved in regulating this process are largely unknown. Here we found that during influenza infection pleural cavity B-1a cells rapidly infiltrated lungs, where they underwent plasmacytic differentiation with enhanced IgM production. This process was promoted by IL-17A signaling via induction of Blimp-1 expression and NF-κB activation in B-1a cells. Deficiency of IL-17A led to severely impaired B-1a-derived antibody production in the respiratory tract, resulting in a deficiency in viral clearance. Transfer of B-1a-derived natural antibodies rescued Il17a ^-/- mice from otherwise lethal infections. Together, we identify a critical function of IL-17A in promoting the plasmacytic differentiation of B-1a cells. Our findings provide new insights into the mechanisms underlying the regulation of pulmonary B-1a cell response against influenza infection.

Author Summary

Influenza infection is highly localized in respiratory tract where immune response is triggered to provide protection from primary infection. Although natural IgM antibodies produced by B-1a cells have long been recognized as first-line protection against influenza, it remains unclear whether B-1a cell response occurs in the lung and what molecular mechanisms regulate this process. We show that airway exposure to influenza causes migration of B-1a cells to lungs for further differentiation into plasma cells with enhanced production of protective IgM antibodies. IL-17A critically regulates this process by driving differentiation of B-1a cells to high-rate IgM producing plasma cells in situ. Thus, IL-17A is a key factor in the local inflammatory milieu that modulates early humoral immunity afforded by B-1a cells.