Notch-activated basophils support intestinal CD4 T cell fate and function during helminth infection

Abstract

Parasitic helminth infections affect over 1 billion people worldwide, underscoring the need to study host-parasite interactions for therapeutic intervention. Helminth infection provokes a Type 2 inflammatory response orchestrated by CD4+ T helper 2 (Th2) cells. In the intestine, Th2s elicit an interleukin-13 (IL-13)-dependent “weep and sweep” response from the epithelium to drive parasite clearance. Tissue-specific cues critically optimize intestinal CD4+ T cell responses, but the exact mechanism the regulate intestinal Th2 responses remain unclear. Basophils, a rare granulocyte, are associated with Th2 function. However, the basophil-dependent signals that support intestinal Th2s are incompletely defined. Previously, we located the Notch signaling pathway in basophil activation during Trichuris muris infection, a mouse model of human whipworm. Here, we show that loss of Notch-activation in basophils results in defective parasite clearance and a blunted Th2 response. We found that basophil-intrinsic Notch was not only required for infection-elicited Th2 cytokine responses, but also for maintaining a broader IL-4 production program across a larger population of diverse intestinal CD4+ T cells. Intestinal CD4+ T cell cytokine production was basophil-dependent in vitro and in vivo, but independent of basophil-secreted factors. Our findings highlight an IL-4 autocrine signaling module that mediates intestinal CD4+ T cell fate and function via direct cell-cell interaction with basophils during helminth infection. These data improve our understanding of the tissue-specific mechanisms required for robust Type 2 immune responses and may inform the development of new therapeutic interventions for helminth infection.