Epithelial-intrinsic IKKα expression regulates group 3 innate lymphoid cell responses and antibacterial immunity

Innate lymphoid cells (ILCs) are critical for maintaining epithelial barrier integrity at mucosal surfaces; however, the tissue-specific factors that regulate ILC responses remain poorly characterized. Using mice with intestinal epithelial cell (IEC)-specific deletions in either inhibitor of kappa B kinase (IKK)alpha or IKK beta, two critical regulators of NF kappa B activation, we demonstrate that IEC-intrinsic IKK alpha expression selectively regulates group 3 ILC (ILC3)-dependent antibacterial immunity in the intestine. Although IKK beta(Delta IEC) mice efficiently controlled Citrobacter rodentium infection, IKK alpha(Delta IEC) mice exhibited severe intestinal inflammation, increased bacterial dissemination to peripheral organs, and increased host mortality. Consistent with weakened innate immunity to C. rodentium, IKK alpha(Delta IEC) mice displayed impaired IL-22 production by ROR gamma t(+) ILC3s, and therapeutic delivery of rIL-22 or transfer of sort-purified IL-22-competent ILCs from control mice could protect IKK alpha(Delta IEC) mice from C. rodentium-induced morbidity. Defective ILC3 responses in IKK alpha(Delta IEC) mice were associated with overproduction of thymic stromal lymphopoietin (TSLP) by IECs, which negatively regulated IL-22 production by ILC3s and impaired innate immunity to C. rodentium. IEC-intrinsic IKK alpha expression was similarly critical for regulation of intestinal inflammation after chemically induced intestinal damage and colitis. Collectively, these data identify a previously unrecognized role for epithelial cell-intrinsic IKK alpha expression and TSLP in regulating ILC3 responses required to maintain intestinal barrier immunity.