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

Cytokines and Lymphoid Development Unit, Institut Pasteur, Paris, France.
The Journal of Immunology (Impact Factor: 5.36). 11/2009; 183(10):6579-87. DOI: 10.4049/jimmunol.0901935
Source: PubMed

ABSTRACT 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-gamma, 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.

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Available from: Jean-Christophe Renauld, Jul 28, 2015
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    • "Among the experimental evidence supporting this thesis, there were the facts that (i) LTi cells lacking NKp46 could differentiate into cells expressing NKRs (including NKp46, NKp44, and NKp30), while maintaining LTi functions, and that (ii) the immature NK cell population purified from fetal lymph nodes has been found to contain transcripts for RORγt and IL-22 (Cupedo et al., 2009). However, despite the induction of NCRs on LTi cells following stimulation in vitro, the cross-linking of NKp46, NKp30, and NKp44 does not trigger cytotoxicity in LTi cells and the ligation of NKp46 is not required for the clearance of C. rodentium infection in mice (Cella et al., 2009; Luci et al., 2009; Satoh-Takayama et al., 2009). Only recently it has been clarified by several reports that, although similar in terms of NCR and RORγt expression, LTi cells and conventional NK lymphocytes belong to separate lineages and have distinct functional and transcriptional profiles both in mice and humans (Crellin et al., 2010; Satoh- Takayama et al., 2010; Vonarbourg et al., 2010; Narni-Mancinelli et al., 2012; Tomasello et al., 2012). "
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    ABSTRACT: Natural cytotoxicity receptors (NCRs) have been classically defined as activating receptors delivering potent signals to Natural Killer (NK) cells in order to lyze harmful cells and to produce inflammatory cytokines. Indeed, the elicitation of NK cell effector functions after engagement of NCRs with their ligands on tumor or virus infected cells without the need for prior antigen recognition is one of the main mechanisms that allow a rapid clearance of target cells. The three known NCRs, NKp46, NKp44, and NKp30, comprise a family of germ-line encoded Ig-like trans-membrane (TM) receptors. Until recently, NCRs were thought to be NK cell specific surface molecules, thus making it possible to easily distinguish NK cells from phenotypically similar cell types. Moreover, it has also been found that the surface expression of NKp46 is conserved on NK cells across mammalian species. This discovery allowed for the use of NKp46 as a reliable marker to identify NK cells in different animal models, a comparison that was not possible before due to the lack of a common and comprehensive receptor repertoire between different species. However, several studies over the recent few years indicated that NCR expression is not exclusively confined to NK cells, but is also present on populations of T as well as of NK-like lymphocytes. These insights raised the hypothesis that the induced expression of NCRs on certain T cell subsets is governed by defined mechanisms involving the engagement of the T cell receptor (TCR) and the action of pro-inflammatory cytokines. In turn, the acquisition of NCRs by T cell subsets is also associated with a functional independence of these Ig-like TM receptors from TCR signaling. Here, we review these novel findings with respect to NCR-mediated functions of NK cells and we also discuss the functional consequences of NCR expression on non-NK cells, with a particular focus on the T cell compartment.
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    • "Importantly, IL-22-specific receptor seems to be expressed only on non-hematopoietic cells including epithelial cells [7]. IL-22 –/– mice develop more severe colitis with marked epithelial damage in the dextran sodium sulfate (DSS)-induced colitis model and Citrobacter rodentium colitis than do control wild-type mice [11] [14]. "
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