Pathogenic Role of an IL-23/γδT17/Neutrophil Axis in Coxsackievirus B3–Induced Pancreatitis

Abstract

Coxsackievirus B is a common cause of viral myocarditis and pancreatitis. IL-17A is intensively involved in the pathogenesis of viral myocarditis. Whether IL-17A plays a role in Coxsackievirus B-induced pancreatitis, characterized by acinar cell destruction and immune infiltration, remains largely unknown. We found a significant, but transient, increase of IL-17A expression and γδT influx in the pancreas of C57BL/6J mice within 3 d following CVB3 infection. The pancreatic IL-17A was mainly produced by Vγ4 γδ T cells, to a lesser extent by CD4⁺ Th17 cells. IL-17A^-/- and TCRδ^-/- mice both reduced their susceptibility to CVB3 infection and pancreatitis severity when compared with the wild-type mice, without altering viral load. mAb depletion of Vγ4γδ T cells significantly improved mice survival and pancreatic pathology via decreasing Th17 expansion and neutrophil influx into the pancreas compared with isotype-treated mice. Transfer of Vγ4γδ T cells from wild-type, but not IL-17^-/-, mice reconstituted TCRδ^-/- mice to produce IL-17 and develop pancreatitis to the level of wild-type mice during CVB3 infection, indicating γδ T IL-17A is required for the onset of viral pancreatitis. IL-23 was robustly induced in the pancreas within the first day of infection. Administration of exogenous rIL-23 to mice increased CVB3 pancreatitis through in vivo expansion of IL-17⁺γδT17 cells at 12 h postinfection. Our findings reveal a key pathogenic role for early-activated γδT17 cells in viral pancreatitis via promoting neutrophil infiltration and Th17 induction. This IL-23/γδT17/neutrophil axis is critically involved in the onset of CVB3 pancreatitis and represents a potential treating target for the disease.