Interleukin-22 (IL-22) signaling in the intestines is critical for promoting tissue-protective functions. However, since a diverse array of cell types (absorptive and secretory epithelium as well as stem cells) express IL-22Ra1, a receptor for IL-22, it has been difficult to determine what cell type(s) specifically respond to IL-22 to mediate intestinal mucosal host defense. Here, we report that IL-22 signaling in the small intestine is positively correlated with Paneth cell differentiation programs. Our Il22Ra1^fl/fl;Lgr5-EGFP-cre^ERT2-specific knockout mice and, independently, our lineage-tracing findings rule out the involvement of Lgr5⁺ intestinal stem cell (ISC)-dependent IL-22Ra1 signaling in regulating the lineage commitment of epithelial cells, including Paneth cells. Using novel Paneth cell-specific IL-22Ra1 knockout mice (Il22Ra1^fl/fl;Defa6-cre), we show that IL-22 signaling in Paneth cells is required for small intestinal host defense. We show that Paneth cell maturation, antimicrobial effector function, expression of specific WNTs, and organoid morphogenesis are dependent on cell-intrinsic IL-22Ra1 signaling. Furthermore, IL-22 signaling in Paneth cells regulates the intestinal commensal bacteria and microbiota-dependent IL-17A immune responses. Finally, we show ISC and, independently, Paneth cell-specific IL-22Ra1 signaling are critical for providing immunity against Salmonella enterica serovar Typhimurium. Collectively, our findings illustrate a previously unknown role of IL-22 in Paneth cell-mediated small intestinal host defense.

肠道中的白介素 22 (IL-22) 信号对于促进组织保护功能至关重要。然而，由于多种细胞类型（吸收和分泌上皮以及干细胞）表达 IL-22Ra1（一种 IL-22 受体），因此很难确定哪些细胞类型对 IL-22 有特异性反应介导肠粘膜宿主防御。在这里，我们报告小肠中的 IL-22 信号与潘氏细胞分化程序呈正相关。我们的Il22Ra1 ^fl/fl ;Lgr5-EGFP-cre ^ERT2特异性敲除小鼠和独立的我们的谱系追踪发现排除了 Lgr5 ^+的参与肠干细胞 (ISC) 依赖性 IL-22Ra1 信号调节上皮细胞（包括潘氏细胞）的谱系定型。使用新型潘氏细胞特异性 IL-22Ra1 基因敲除小鼠 ( Il22Ra1 ^fl/fl ;Defa6-cre )，我们表明潘氏细胞中的 IL-22 信号传导是小肠宿主防御所必需的。我们表明，Paneth 细胞成熟、抗菌效应子功能、特定 WNT 的表达和类器官形态发生都依赖于细胞内在的 IL-22Ra1 信号传导。此外，Paneth 细胞中的 IL-22 信号调节肠道共生细菌和微生物群依赖性 IL-17A 免疫反应。最后，我们展示了 ISC 和独立的 Paneth 细胞特异性 IL-22Ra1 信号对于提供针对肠道沙门氏菌的免疫力至关重要鼠伤寒血清型。总的来说，我们的研究结果说明了 IL-22 在潘氏细胞介导的小肠宿主防御中的一个以前未知的作用。