Mammary epithelial IL-2 is critical for NK cell-mediated local tumor immunosurveillance 3392

Abstract Description Interleukin-2 (IL-2) is a pleiotropic cytokine playing important roles in both lymphoid and non-lymphoid cells to maintain tissue-immune homeostasis. Until now, active T cells are known to be the primary cellular sources of IL-2 although natural killer (NK) cells, dendritic cells, and intestinal innate lymphoid cells have also been found to produce IL-2 in different contexts. Datamining our previously published mouse mammary gland single-cell RNA-seq dataset revealed significant Il2 expression in mammary epithelial cells, which we validated by detecting the IL-2 protein in a flow cytometric analysis. We found that prolactin induces Il2 expression in mammary epithelial cells by activating the STAT5 signaling pathway. To specifically evaluate the in vivo significance of mammary epithelial IL-2, we conditionally deleted IL2 within these cells by crossing MMTV-Cre and IL2fl/fl mice. We found that mammary epithelial IL-2 is required for the maintenance of NK cell number and function in the mouse mammary gland. Loss of NK cells in the epithelial IL-2-deficient mammary tissue was consistent with compromised tumor immunosurveillance evidenced by expansion of luminal mammary epithelial cells in young epithelial IL-2 KO mice culminating in mammary tumor development as they grew old. Our results establish mammary epithelial cells as novel producers of IL-2, critical for NK cell-mediated cancer immunosurveillance in the mammary tissue. Funding Sources NIH grants CA200673, CA203834, and CA260239 Topic Categories Cytokines and Chemokines and Their Receptors (CCR)