The IL-33/ST2 axis and tissue Treg maintain epithelial homeostasis and restrain cancer development in the skin

Interleukin (IL)-33 is constitutively expressed in many epithelial tissues at steady state and signals through the receptor, ST2. IL-33 is released upon tissue injury and functions as an endogenous danger signal to alert the immune system to tissue damage. Here we investigate the physiological role of the IL-33/ST2 axis in skin homeostasis and cancer development. We show that the expression of IL-33 differentiates malignant from normal and benign human tissues and that in mouse models of cutaneous squamous cell carcinoma the IL-33/ST2 axis protects against carcinogenesis. Tissue regulatory T cells (Tregs) are the predominant cells expressing ST2 in the skin and localize around the hair follicle and IL-33⁺ epithelial cells (ECs). Adoptive transfer experiments demonstrate that skin Tregs regulate EC differentiation, minimizing mutational load and restraining cancer development after exposure to an environmental carcinogen. Our findings indicate an important role for EC-Treg cross-talk as an early checkpoint for containing tissue damage and carcinogenesis.