The non-canonical RORγt–IL-17C/IL-17RE axis drives hepatic fibrosis in Schistosoma japonicum infection through CD4+ T cell–NK cell crosstalk

Schistosomiasis affects over 240 million people worldwide, and hepatic fibrosis is its primary cause of morbidity and mortality. In Schistosoma japonicum infection, liver fibrosis arises from dysregulated host immune responses to parasite eggs trapped in hepatic sinusoids. Although CD4 + T cell-intrinsic RORγt is a known driver of this pathology, the protection conferred by T cell-specific Rorc deletion is not fully recapitulated by IL-17A or IL-23 neutralization, suggesting additional RORγt effector pathways. Here we identify the IL-17C/IL-17RE axis, previously unstudied in helminth infection, as a driver of S. japonicum -induced hepatic fibrosis through pathogenic crosstalk between CD4 + T cells and natural killer (NK) cells. Using germline and conditional knockout mice, we show that RORγt binds a promoter-proximal element of Il17re and is required for its expression in CD4 + T cells, consistent with direct transcriptional regulation. Hepatocytes are the major functional source of IL-17C during infection, induced by a feed-forward loop involving CD4 + T cell-derived TNF-α and IL-17A. IL-17C signals through IL-17RE on CD4 + T cells to promote IL-2 production via the ACT1–NF-κB/ERK cascade; this IL-2 in turn drives hepatic NK cell maturation, activation, and TRAIL-mediated cytotoxicity, the downstream effectors of liver injury and fibrosis. Germline or CD4 + T cell-specific deletion of Il17c or Il17re alleviates hepatic pathology without substantially affecting parasite burden. Antibody-mediated blockade of IL-17RE, administered therapeutically, ameliorates established acute and chronic hepatic fibrosis in mice. These findings define an IL-17C/IL-17RE-dependent inflammatory cascade in schistosomiasis-associated liver fibrosis and support this axis as a candidate therapeutic target.