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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0901935v1 183/10/6579    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Satoh-Takayama, N. Articles by Di Santo, J. P. PubMed PubMed Citation Articles by Satoh-Takayama, N. Articles by Di Santo, J. P.

The Natural Cytotoxicity Receptor NKp46 Is Dispensable for IL-22-Mediated Innate Intestinal Immune Defense against Citrobacter rodentium¹

Naoko Satoh-Takayama,^* Laure Dumoutier, Sarah Lesjean-Pottier,^* Vera S. G. Ribeiro,^* Ofer Mandelboim, Jean-Christophe Renauld, Christian A. J. Vosshenrich,^* and James P. Di Santo^2*

^*Cytokines and Lymphoid Development Unit, Institut Pasteur, Paris, France; INSERM Unité 668, Paris, France; Ludwig Institute for Cancer Research, Experimental Medicine Unit, Universite Catholique de Louvain, Brussels, Belgium; and The Lautenberg Center for General and Tumor Immunology, Hebrew University-Hadassah Medical School, Jerusalem, Israel

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-, 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants to J.P.D. from the Institut Pasteur, INSERM, and as an "Equipe Labelisé" by the Ligue Nationale Contre le Cancer. N.S.-T. was the recipient of fellowship from The Uehara Memorial Foundation, Japan.

² Address correspondence and reprint requests to Dr. James P. Di Santo, Cytokines and Lymphoid Development Unit, Institut Pasteur, Paris, France, F-75724. E-mail address: disanto{at}pasteur.fr

³ Abbreviations used in this paper: NCR, natural cytotoxicity receptor; LTi, lymphoid tissue inducer; LPL, lamina propria lymphocyte; WT, wild type.

⁴ The online version of this article contains supplemental material.