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: 4.92). 11/2009; 183(10):6579-87. DOI: 10.4049/jimmunol.0901935
Source: PubMed


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, Oct 04, 2015
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    • "ILC3s produce the Th17 signature cytokines IL-17 and/or IL-22 (64–69). ILC3s include Lineage− (Lin)RORγt+ CD4+ Lti-like cells originally described in the 1990s (70), Lin− RORγt+ CD4− Lti-like cells, NCR+ ILC3s originally named NK-22 (65), and colonic Sca1+ Thy1high ILCs (71). "
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    ABSTRACT: For a long time, natural killer (NK) cells were thought to be the only innate immune lymphoid population capable of responding to invading pathogens under the influence of changing environmental cues. In the last few years, an increasing amount of evidence has shown that a number of different innate lymphoid cell (ILC) populations found at mucosal sites rapidly respond to locally produced cytokines in order to establish or maintain homeostasis. These ILC populations closely mirror the phenotype of adaptive T helper subsets in their repertoire of secreted soluble factors. Early in the immune response, ILCs are responsible for setting the stage to mount an adaptive T cell response that is appropriate for the incoming insult. Here, we review the diversity of ILC subsets and discuss similarities and differences between ILCs and NK cells in function and key transcriptional factors required for their development.
    Frontiers in Immunology 06/2014; 5:282. DOI:10.3389/fimmu.2014.00282
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    • "Yet, in contrast with our findings, NK cells, characterized as NK1.1+CD3− cells, were shown to modestly produce IL-22, but not IL-17, when cultured in the presence of IL-23 [39]. One possible explanation that may help reconcile these two findings, is that the NK1.1+CD3− cells may include a subset of ILC3 cells that are responsive to IL-23 [40], [41]. This issue will likely be resolved as more tools become available to study IL-12Rβ2 expression. "
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    ABSTRACT: IL-12 and IL-23 cytokines respectively drive Th1 and Th17 type responses. Yet, little is known regarding the biology of these receptors. As the IL-12 and IL-23 receptors share a common subunit, it has been assumed that these receptors are co-expressed. Surprisingly, we find that the expression of each of these receptors is restricted to specific cell types, in both mouse and human. Indeed, although IL-12Rβ2 is expressed by NK cells and a subset of γδ T cells, the expression of IL-23R is restricted to specific T cell subsets, a small number of B cells and innate lymphoid cells. By exploiting an IL-12- and IL-23-dependent mouse model of innate inflammation, we demonstrate an intricate interplay between IL-12Rβ2 NK cells and IL-23R innate lymphoid cells with respectively dominant roles in the regulation of systemic versus local inflammatory responses. Together, these findings support an unforeseen lineage-specific dichotomy in the in vivo role of both the IL-12 and IL-23 pathways in pathological inflammatory states, which may allow more accurate dissection of the roles of these receptors in chronic inflammatory diseases in humans.
    PLoS ONE 02/2014; 9(2):e89092. DOI:10.1371/journal.pone.0089092 · 3.23 Impact Factor
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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.
    Frontiers in Immunology 03/2013; 4(69):69. DOI:10.3389/fimmu.2013.00069
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