Notch-activated basophils support intestinal CD4+ T cell fate and function during helminth infection
Helminth infections affect billions of people worldwide and cause substantial morbidity.  Intestinal helminth infection provokes Type 2 inflammation orchestrated by CD4+ T  helper 2 (Th2) cells. Th2s produce interleukin (IL)-4 and IL-13 that prompt an epithelial  “weep and sweep” response to drive parasite clearance. Tissue-specific cues optimize  CD4+ T cell responses, but the mechanisms regulating intestinal Th2 responses  remain unclear. Previously, we identified that the Notch signaling pathway in basophils,  rare granulocytes, drove effective parasite clearance and an optimal Th2 response  during Trichurismuris infection, a mouse model of human whipworm. Here we report  basophil-intrinsic Notch was required for infection-elicited Th2 cytokine responses and  a broader IL-4 production program across intestinal CD4+ T cell subsets. In vitro,  basophils supported CD4+ T cell cytokine production in a contact-dependent manner,  independent of basophil-secreted factors, and was dependent on autocrine IL-4  production from CD4+ T cells. In vivo, basophil-intrinsic Notch mediated basophil-Th2  cell interactions in the cecum during infection. Thus, Notch-programmed basophils act  in a contact-dependent manner to optimize intestinal CD4+ T cell function during  helminth infection. These findings improve our understanding of the tissue-specific  mechanisms regulating intestinal CD4+ T cell responses at inflamed mucosal barriers  during Type 2 immunity. Overall design: Bulk RNA-seq of cecum CD4+ T cells from Mcpt8-Cre- and Mcpt8-Cre+ DNMAMLF/F mice at steady state or during T. muris infection.