The natural cytotoxicity receptor NKp46 is dispensable for IL-22-mediated innate intestinal immune defense against Citrobacter rodentium

Natural cytotoxicity receptors (including NKp30, NKp44, and NKp46 in humans and NKp46 in mice) are type I transmembrane proteins that signal NK cell activation via ITAM-containing adapter proteins in response to stress- and pathogen-induced ligands. Although murine NKp46 expression (encoded by Ncr1) was thought to be predominantly restricted to NK cells, the identification of distinct intestinal NKp46⁺ cell subsets that express the transcription factor Rorc and produce IL-22 suggests a broader function for NKp46 that could involve intestinal homeostasis and immune defense. Using mice carrying a GFP-modified Ncr1 allele, we found normal numbers of gut CD3 ^-GFP⁺ cells with a similar cell surface phenotype and subset distribution in the absence of Ncr1. Splenic and intestinal CD3 ^-NKp46⁺ cell subsets showed distinct patterns of cytokine secretion (IFN-γ, IL-22) following activation via NK1.1, NKp46, IL-12 plus IL-18, or IL-23. However, IL-22 production was sharply restricted to intestinal CD3^-GFP⁺ cells with the CD127⁺NK1.1 ^- phenotype and could be induced in an Ncr1-independent fashion. Because NKp46 ligands can trigger immune activation in the context of infectious pathogens, we assessed the response of wild-type and Ncr-1-deficient Rag2 ^-/- mice to the enteric pathogen Citrobacter rodentium. No differences in the survival or clinical score were observed in C. rodentium-infected Rag2^-/- mice lacking Ncr1, indicating that NKp46 plays a redundant role in the differentiation of intestinal IL-22⁺ cells that mediate innate defense against this pathogen. Our results provide further evidence for functional heterogeneity in intestinal NKp46⁺ cells that contrast with splenic NK cells.