Goblet cell-derived resistin-like molecule β augments CD4⁺ T cell production of IFN-γ and infection-induced intestinal inflammation

The secreted goblet cell-derived protein resistin-like molecule β (RELMβ) has been implicated in divergent functions, including a direct effector function against parasitic helminths and a pathogenic function in promoting inflammation in models of colitis and ileitis. However, whether RELMβ influences CD4⁺ T cell responses in the intestine is unknown. Using a natural model of intestinal inflammation induced by chronic infection with gastrointestinal helminth Trichuris muris, we identify dual functions for RELMβ in augmenting CD4⁺ Th1 cell responses and promoting infection-induced intestinal inflammation. Following exposure to low-dose Trichuris, wild-type C57BL/6 mice exhibit persistent infection associated with robust IFN-γ production and intestinal inflammation. In contrast, infected RELMβ^-/- mice exhibited a significantly reduced expression of parasite-specific CD4⁺ T cell-derived IFN-γ and TNF-α and failed to develop Trichuris-induced intestinal inflammation. In in vitro T cell differentiation assays, recombinant RELMβ activated macrophages to express MHC class II and secrete IL-12/23p40 and enhanced their ability to mediate Ag-specific IFN-γexpression in CD4 ⁺ T cells. Taken together, these data suggest that goblet cell-macrophage cross-talk, mediated in part by RELMβ, can promote adaptive CD4⁺ T cell responses and chronic inflammation following intestinal helminth infection.