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• W2009035135 abstract "With the goal in mind to define how interleukin-15 (IL-15) contributes to acute intestinal inflammation, we have used a mouse model of ileitis induced by oral infection with Toxoplasma gondii. We observed that a crosstalk between IL-15 and interleukin-18 (IL-18) promoted intestinal recruitment of inflammatory monocytes, where these cells participated in parasite control but also in tissue damage. A stromal source of IL-15 controlled the development of lamina propria NKp46+NK1.1+ cells, whereas IL-18 produced during T. gondii infection stimulated their production of the chemokine CCL3. In turn, CCL3 attracted inflammatory monocytes via their chemokine receptor CCR1, which was indispensable for their recruitment into the inflamed gut. Collectively, these results identify the IL-15-dependent subset of intestinal NKp46+ cells as an important source of CCL3, which can amplify intestinal inflammation via the recruitment of CCR1+ inflammatory monocytes. Preliminary evidence suggests that this pathway might operate in Crohn's disease. With the goal in mind to define how interleukin-15 (IL-15) contributes to acute intestinal inflammation, we have used a mouse model of ileitis induced by oral infection with Toxoplasma gondii. We observed that a crosstalk between IL-15 and interleukin-18 (IL-18) promoted intestinal recruitment of inflammatory monocytes, where these cells participated in parasite control but also in tissue damage. A stromal source of IL-15 controlled the development of lamina propria NKp46+NK1.1+ cells, whereas IL-18 produced during T. gondii infection stimulated their production of the chemokine CCL3. In turn, CCL3 attracted inflammatory monocytes via their chemokine receptor CCR1, which was indispensable for their recruitment into the inflamed gut. Collectively, these results identify the IL-15-dependent subset of intestinal NKp46+ cells as an important source of CCL3, which can amplify intestinal inflammation via the recruitment of CCR1+ inflammatory monocytes. Preliminary evidence suggests that this pathway might operate in Crohn's disease. CCR1 is instrumental for intestinal recruitment of inflammatory monocytes CCL3 is produced by the intestinal subset of IL-15-dependent NKp46+NK1.1+ cells NK cell-dependent CCL3 enhances intestinal recruitment of inflammatory monocytes IL-18 stimulates intestinal CCL3 production during T. gondii-induced ileitis Interleukin 15 (IL-15) is a pleiotropic cytokine with a large range of functions at the interface between innate and adaptive immunity. An essential role in the differentiation, survival, and/or activation of natural killer (NK), NKT cells, γδ T cell receptor+ (TCR) intraepithelial lymphocytes (IELs), and CD8+ memory T cells is firmly established in mice lacking IL-15 or IL-15 receptor α chain (IL-15Rα) (Kennedy et al., 2000Kennedy M.K. Glaccum M. Brown S.N. Butz E.A. Viney J.L. Embers M. Matsuki N. Charrier K. Sedger L. Willis C.R. et al.Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice.J. Exp. Med. 2000; 191: 771-780Crossref PubMed Scopus (1338) Google Scholar, Lodolce et al., 1998Lodolce J.P. Boone D.L. Chai S. Swain R.E. Dassopoulos T. Trettin S. Ma A. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation.Immunity. 1998; 9: 669-676Abstract Full Text Full Text PDF PubMed Scopus (1095) Google Scholar) or, conversely, overexpressing IL-15 (Fehniger et al., 2001Fehniger T.A. Suzuki K. Ponnappan A. VanDeusen J.B. Cooper M.A. Florea S.M. Freud A.G. Robinson M.L. Durbin J. Caligiuri M.A. Fatal leukemia in interleukin 15 transgenic mice follows early expansions in natural killer and memory phenotype CD8+ T cells.J. Exp. Med. 2001; 193: 219-231Crossref PubMed Scopus (317) Google Scholar, Ohta et al., 2002Ohta N. Hiroi T. Kweon M.N. Kinoshita N. Jang M.H. Mashimo T. Miyazaki J. Kiyono H. IL-15-dependent activation-induced cell death-resistant Th1 type CD8 alpha beta+NK1.1+ T cells for the development of small intestinal inflammation.J. Immunol. 2002; 169: 460-468Crossref PubMed Scopus (81) Google Scholar). In humans, IL-15 is thought to participate in the pathogenesis of a spectrum of inflammatory or autoimmune diseases. In rheumatoid arthritis, increased IL-15 concentrations are found in the synovium, and IL-15 is suggested to exert direct chemoattractant activity toward synovial T cells to stimulate their proliferation and their production of tumor necrosis factor-α (TNF-α). IL-15-activated T cells can also stimulate TNF-α production by peripheral blood monocytes and tissue macrophages via a contact-dependent mechanism (McInnes et al., 1996McInnes I.B. al-Mughales J. Field M. Leung B.P. Huang F.P. Dixon R. Sturrock R.D. Wilkinson P.C. Liew F.Y. The role of interleukin-15 in T-cell migration and activation in rheumatoid arthritis.Nat. Med. 1996; 2: 175-182Crossref PubMed Scopus (425) Google Scholar, McInnes et al., 1997McInnes I.B. Leung B.P. Sturrock R.D. Field M. Liew F.Y. Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-alpha production in rheumatoid arthritis.Nat. Med. 1997; 3: 189-195Crossref PubMed Scopus (435) Google Scholar). A similar mechanism has been suggested in Crohn's disease (CD) (Liu et al., 2000Liu Z. Geboes K. Colpaert S. D'Haens G.R. Rutgeerts P. Ceuppens J.L. IL-15 is highly expressed in inflammatory bowel disease and regulates local T cell-dependent cytokine production.J. Immunol. 2000; 164: 3608-3615Crossref PubMed Scopus (164) Google Scholar). In CD, increased numbers of IL-15-producing mononuclear cells are observed in the intestinal lamina propria (LP), and augmented serum concentrations of IL-15 are found to predict patients' response to anti-TNF-α treatment (Bouchaud et al., 2010Bouchaud G. Mortier E. Flamant M. Barbieux I. Plet A. Galmiche J.P. Jacques Y. Bourreille A. Interleukin-15 and its soluble receptor mediate the response to infliximab in patients with Crohn's disease.Gastroenterology. 2010; 138: 2378-2387Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). Alternatively, we and others have suggested that in celiac disease, chronic overexpression of IL-15 by intestinal epithelial cells drives the expansion and activation of cytotoxic CD8+αβTCR+ IELs that may destroy epithelial cells via an NK-like mechanism involving the NKG2D receptor (Hüe et al., 2004Hüe S. Mention J.J. Monteiro R.C. Zhang S. Cellier C. Schmitz J. Verkarre V. Fodil N. Bahram S. Cerf-Bensussan N. Caillat-Zucman S. A direct role for NKG2D/MICA interaction in villous atrophy during celiac disease.Immunity. 2004; 21: 367-377Abstract Full Text Full Text PDF PubMed Scopus (566) Google Scholar, Meresse et al., 2004Meresse B. Chen Z. Ciszewski C. Tretiakova M. Bhagat G. Krausz T.N. Raulet D.H. Lanier L.L. Groh V. Spies T. et al.Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease.Immunity. 2004; 21: 357-366Abstract Full Text Full Text PDF PubMed Scopus (649) Google Scholar). This mechanism has also been invoked to explain epithelial destruction in a mouse model of acute intestinal inflammation induced by intraperitoneal injection of poly(I:C) (Zhou et al., 2007Zhou R. Wei H. Sun R. Zhang J. Tian Z. NKG2D recognition mediates Toll-like receptor 3 signaling-induced breakdown of epithelial homeostasis in the small intestines of mice.Proc. Natl. Acad. Sci. USA. 2007; 104: 7512-7515Crossref PubMed Scopus (55) Google Scholar). Finally, other studies suggest that IL-15 might impair immunoregulatory mechanisms and thereby promote CD8+ and CD4+ T cell effector responses (Ben Ahmed et al., 2009Ben Ahmed M.B. Belhadj Hmida N. Moes N. Buyse S. Abdeladhim M. Louzir H. Cerf-Bensussan N. IL-15 renders conventional lymphocytes resistant to suppressive functions of regulatory T cells through activation of the phosphatidylinositol 3-kinase pathway.J. Immunol. 2009; 182: 6763-6770Crossref PubMed Scopus (95) Google Scholar, Benahmed et al., 2007Benahmed M. Meresse B. Arnulf B. Barbe U. Mention J.J. Verkarre V. Allez M. Cellier C. Hermine O. Cerf-Bensussan N. Inhibition of TGF-beta signaling by IL-15: a new role for IL-15 in the loss of immune homeostasis in celiac disease.Gastroenterology. 2007; 132: 994-1008Abstract Full Text Full Text PDF PubMed Scopus (148) Google Scholar, DePaolo et al., 2011DePaolo R.W. Abadie V. Tang F. Fehlner-Peach H. Hall J.A. Wang W. Marietta E.V. Kasarda D.D. Waldmann T.A. Murray J.A. et al.Co-adjuvant effects of retinoic acid and IL-15 induce inflammatory immunity to dietary antigens.Nature. 2011; 471: 220-224Crossref PubMed Scopus (311) Google Scholar, Hmida et al., 2012Hmida N.B. Ben Ahmed M. Moussa A. Rejeb M.B. Said Y. Kourda N. Meresse B. Abdeladhim M. Louzir H. Cerf-Bensussan N. Impaired control of effector T cells by regulatory T cells: a clue to loss of oral tolerance and autoimmunity in celiac disease?.Am. J. Gastroenterol. 2012; 107: 604-611Crossref PubMed Scopus (80) Google Scholar). To delineate the role of IL-15 in intestinal inflammation, we have used a mouse model of acute ileitis induced by oral infection of C57BL/6 mice with Toxoplasma gondii. In this strain of mice, the intestinal immune reaction is necessary to eliminate the parasite but is excessive and results in lethal jejuno-ileitis. Intestinal inflammation depends on the activation of CD4+ T helper 1 (Th1) intestinal LP cells specific for the triggering antigen (Liesenfeld et al., 1996Liesenfeld O. Kosek J. Remington J.S. Suzuki Y. Association of CD4+ T cell-dependent, interferon-gamma-mediated necrosis of the small intestine with genetic susceptibility of mice to peroral infection with Toxoplasma gondii.J. Exp. Med. 1996; 184: 597-607Crossref PubMed Scopus (277) Google Scholar, Rachinel et al., 2004Rachinel N. Buzoni-Gatel D. Dutta C. Mennechet F.J. Luangsay S. Minns L.A. Grigg M.E. Tomavo S. Boothroyd J.C. Kasper L.H. The induction of acute ileitis by a single microbial antigen of Toxoplasma gondii.J. Immunol. 2004; 173: 2725-2735Crossref PubMed Scopus (64) Google Scholar), but several complementary mechanisms are believed to participate in both pathogen exclusion and inflammation, notably the activation of CD8+αβTCR+ IELs (Chardès et al., 1994Chardès T. Buzoni-Gatel D. Lepage A. Bernard F. Bout D. Toxoplasma gondii oral infection induces specific cytotoxic CD8 alpha/beta+ Thy-1+ gut intraepithelial lymphocytes, lytic for parasite-infected enterocytes.J. Immunol. 1994; 153: 4596-4603PubMed Google Scholar, Egan et al., 2009Egan C.E. Craven M.D. Leng J. Mack M. Simpson K.W. Denkers E.Y. CCR2-dependent intraepithelial lymphocytes mediate inflammatory gut pathology during Toxoplasma gondii infection.Mucosal Immunol. 2009; 2: 527-535Crossref PubMed Scopus (39) Google Scholar) and that of inflammatory monocytes (Dunay et al., 2008Dunay I.R. Damatta R.A. Fux B. Presti R. Greco S. Colonna M. Sibley L.D. Gr1(+) inflammatory monocytes are required for mucosal resistance to the pathogen Toxoplasma gondii.Immunity. 2008; 29: 306-317Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar). Furthermore, a prior report with Il15−/− mice has suggested that IL-15 may be necessary for both protection and inflammation during T. gondii infection (Combe et al., 2006Combe C.L. Moretto M.M. Schwartzman J.D. Gigley J.P. Bzik D.J. Khan I.A. Lack of IL-15 results in the suboptimal priming of CD4+ T cell response against an intracellular parasite.Proc. Natl. Acad. Sci. USA. 2006; 103: 6635-6640Crossref PubMed Scopus (35) Google Scholar). We have shown herein that IL-15, although not required to control parasite replication, is necessary for the development of inflammation and tissue destruction. The proinflammatory effect of IL-15 did not depend on IEL activation and IL-15 was dispensable for the development of the CD4+ Th1 cell response. In contrast, IL-15 amplified the recruitment of CCR1+ inflammatory monocytes. We have shown that a nonhematopoietic source of IL-15 controlled the development and function of a subset of intestinal NKp46+ innate lymphoid cells that produced CCL3 in response to inflammatory cytokines, and notably to IL-18 during T. gondii infection. In turn, CCL3 attracted CCR1+ inflammatory monocytes via the CCR1 receptor, which was indispensable for the recruitment of the latter cells toward the inflamed gut. Preliminary evidence suggests that this pathway may operate in CD. In wild-type male C57BL/6 mice, oral gavage with 35 cysts of T. gondii strain 76K induced a severe jejuno-ileitis leading rapidly to death (Figure 1A ). In Il15−/− mice, oral infection induced weight loss (Figure S1A available online), but all animals survived the early phase of infection and the severity of intestinal lesions was markedly attenuated (Figure 1B). In contrast, no increase in parasite load was observed in the intestine, mesenteric lymph nodes (MLNs) (Figures 1C and 1D), liver, or spleen of Il15−/− mice (Figures S1C and S1D) and the majority of Il15−/− mice were still alive at 40 days postinfection (p.i.) (Figure S1B), indicating that IL-15 is redundant to control parasite replication but contributes to intestinal inflammation in this model. These results differentiate the role of IL-15 from that of interferon-γ (IFN-γ), which is necessary not only to induce intestinal inflammation (Liesenfeld et al., 1996Liesenfeld O. Kosek J. Remington J.S. Suzuki Y. Association of CD4+ T cell-dependent, interferon-gamma-mediated necrosis of the small intestine with genetic susceptibility of mice to peroral infection with Toxoplasma gondii.J. Exp. Med. 1996; 184: 597-607Crossref PubMed Scopus (277) Google Scholar) but also to control local and systemic replication of the parasite (Figures 1C and 1D). IL-15 can be produced by many cell types, including enterocytes, dendritic cells (DCs), and macrophages. Accordingly, upregulation of IL-15 mRNA after T. gondii infection was observed in enterocytes as well as in CD11c+CD11b+/− DCs isolated from LP and MLN (Figures S1E–S1G). To determine which source of IL-15 controls the severity of the ileitis, the outcome of T. gondii infection was compared in hematopoietic chimeras. As shown in Figure 1E, all irradiated WT mice reconstituted with Il15−/− bone marrow (BM) developed a lethal ileitis whereas 80% of Il15−/− mice reconstituted with WT BM survived (p < 0.005), indicating that a nonhematopoietic source of IL-15, presumably epithelial cells, controls the intensity of intestinal inflammation. A stromal source of IL-15 is necessary for the expansion of CD8αα+ IELs and more particularly of γδTCR+ IELs (Schluns et al., 2004Schluns K.S. Nowak E.C. Cabrera-Hernandez A. Puddington L. Lefrançois L. Aguila H.L. Distinct cell types control lymphoid subset development by means of IL-15 and IL-15 receptor alpha expression.Proc. Natl. Acad. Sci. USA. 2004; 101: 5616-5621Crossref PubMed Scopus (134) Google Scholar). Accordingly, γδTCR+ IELs were almost absent in Il15−/− mice reconstituted or not with WT BM, which developed an attenuated form of ileitis (Figure 2A ). Adoptive transfer of 5 × 106 γδTCR+ IELs did not aggravate the course of the ileitis in Il15−/− recipients (Figure S2A) and, in keeping with previous observations (Liesenfeld et al., 1996Liesenfeld O. Kosek J. Remington J.S. Suzuki Y. Association of CD4+ T cell-dependent, interferon-gamma-mediated necrosis of the small intestine with genetic susceptibility of mice to peroral infection with Toxoplasma gondii.J. Exp. Med. 1996; 184: 597-607Crossref PubMed Scopus (277) Google Scholar), Tcrd−/− mice developed a lethal ileitis (Figure 2B). Therefore, it is unlikely that γδTCR+ IELs contributed to IL-15-driven inflammation. Nonhematopoietic cell-derived IL-15 might also activate cytotoxic CD8+αβTCR+ IELs. After oral infection with T. gondii, this subset of IELs can kill T. gondii-infected targets in vitro (Chardès et al., 1994Chardès T. Buzoni-Gatel D. Lepage A. Bernard F. Bout D. Toxoplasma gondii oral infection induces specific cytotoxic CD8 alpha/beta+ Thy-1+ gut intraepithelial lymphocytes, lytic for parasite-infected enterocytes.J. Immunol. 1994; 153: 4596-4603PubMed Google Scholar). In addition, IL-15 can stimulate IEL cytotoxicity by inducing perforin and granzymes (Mention et al., 2003Mention J.J. Ben Ahmed M. Bègue B. Barbe U. Verkarre V. Asnafi V. Colombel J.F. Cugnenc P.H. Ruemmele F.M. McIntyre E. et al.Interleukin 15: a key to disrupted intraepithelial lymphocyte homeostasis and lymphomagenesis in celiac disease.Gastroenterology. 2003; 125: 730-745Abstract Full Text Full Text PDF PubMed Scopus (382) Google Scholar) or by enhancing expression of and/or signaling via the activating NKG2D receptor (Hüe et al., 2003Hüe S. Monteiro R.C. Berrih-Aknin S. Caillat-Zucman S. Potential role of NKG2D/MHC class I-related chain A interaction in intrathymic maturation of single-positive CD8 T cells.J. Immunol. 2003; 171: 1909-1917Crossref PubMed Scopus (49) Google Scholar, Meresse et al., 2004Meresse B. Chen Z. Ciszewski C. Tretiakova M. Bhagat G. Krausz T.N. Raulet D.H. Lanier L.L. Groh V. Spies T. et al.Coordinated induction by IL15 of a TCR-independent NKG2D signaling pathway converts CTL into lymphokine-activated killer cells in celiac disease.Immunity. 2004; 21: 357-366Abstract Full Text Full Text PDF PubMed Scopus (649) Google Scholar). We found that NKG2D expression increased significantly in LP CD8+αβTCR+ lymphocytes from WT but not Il15−/− mice (Figure S2B) but IELs remained largely NKG2D negative during T. gondii ileitis (data not shown) and administration of a blocking NKG2D antibody (Ogasawara et al., 2004Ogasawara K. Hamerman J.A. Ehrlich L.R. Bour-Jordan H. Santamaria P. Bluestone J.A. Lanier L.L. NKG2D blockade prevents autoimmune diabetes in NOD mice.Immunity. 2004; 20: 757-767Abstract Full Text Full Text PDF PubMed Scopus (260) Google Scholar) did not modify the course of the disease in WT mice (Figure S2C). Finally, neither the course of the ileitis (Figures 2C and 2D) nor the parasitic load (data not shown) were modified in either Prf1−/− or B2m−/− mice, arguing against a major contribution of cytotoxic CD8+ T cells to early protection against the parasite. These results also point to a need for IL-15-mediated amplification of intestinal inflammation in this acute model. A previous study suggested that IL-15 promotes a specific Th1 cell response during T. gondii infection (Combe et al., 2006Combe C.L. Moretto M.M. Schwartzman J.D. Gigley J.P. Bzik D.J. Khan I.A. Lack of IL-15 results in the suboptimal priming of CD4+ T cell response against an intracellular parasite.Proc. Natl. Acad. Sci. USA. 2006; 103: 6635-6640Crossref PubMed Scopus (35) Google Scholar). This response is thought to be initiated by infected mucosal CD11c+ DCs, which migrate to MLNs between days 3 and 7 p.i. (Courret et al., 2006Courret N. Darche S. Sonigo P. Milon G. Buzoni-Gâtel D. Tardieux I. CD11c- and CD11b-expressing mouse leukocytes transport single Toxoplasma gondii tachyzoites to the brain.Blood. 2006; 107: 309-316Crossref PubMed Scopus (298) Google Scholar) and elicit specific CD4+ Th1 cells that home to the LP. IFN-γ mRNA and protein expression were therefore compared on days 0, 3, 5, and 7 in jejunal biopsies (Figures S2D and S2E) and in cells isolated from MLN and LP of Il15−/− and WT mice (Figures 2E and 2F, left). Upregulation of IFN-γ mRNA was slightly delayed in MLN lymphocytes of Il15−/− mice and a small amount of IFN-γ secretion was induced by soluble T. gondii antigen (STAg) from LPL in WT but not Il15−/− mice on day 5 (Figures 2E and 2G). Yet, on day 7, LPL from both groups of animals spontaneously produced massive and comparable amounts of IFN-γ, which did not further increase in the presence of STAg (Figure 2H). Furthermore, no difference could be demonstrated between WT and Il15−/− mice in the percentages of IFN-γ-producing CD4+ T cells in either the MLN or LPL at all time points (Figures 2E and 2F, right). Finally, no difference could be demonstrated in the percentage of CD4+CD25+Foxp3+ T cells in the LP of WT and Il15−/− mice on days 5 and 7 p.i. (Figure S2F). Altogether, these results indicate that WT and Il15−/− mice develop comparable CD4+ Th1 cell responses, a finding in keeping with comparable parasitic burden in both animal groups. Inflammation in WT and Il15−/− mice was next assessed by comparing intestinal IL-1β, TNF-α, and IL-6 production during infection. Upregulation of IL-1β, TNF-α, and IL-6 mRNA was first observed in intestinal biopsies and in isolated LP cells on day 5 p.i. and increased markedly on day 7 when copious amounts of IL-1β, TNF-α, and IL-6 were spontaneously released in the supernatants of biopsies (Figures S3A and S3B) or isolated LP (Figures 3A and S3C). Upregulation of inflammatory cytokines was observed in all mice but was significantly higher in WT than in Il15−/− mice. To identify the cellular source of inflammatory cytokines, LP cells were isolated from infected WT mice on day 7 and sorted into CD3+, CD19+, CD3−NK1.1+, or CD45+CD3−CD19−NK1.1− cells. Reverse transcriptase-polymerase chain reaction (RT-PCR) and ELISA analysis showed that IL-1β, TNF-α, and IL-6 mRNA and IL-1β and TNF-α secretion were upregulated only in CD45+CD3−CD19−NK1.1− LP cells (Figures 3B and S3D). The latter subset was further separated into neutrophils (Ly6G+Ly6C+CD11b+), inflammatory monocytes (Ly6ChiF4/80+Ly6G−CD11b+CD11c−), and resident macrophages (F4/80+CD11b+Ly6C−Ly6G−) and their secretion tested by ELISA. Inflammatory monocytes released conspicuous amounts of IL-1β, TNF-α, and IL-6 whereas much smaller amounts of TNF-α and IL-6 were produced by neutrophils and macrophages, respectively (Figure S3E). Flow cytometry analysis confirmed that inflammatory monocytes were the main producers of TNF-α (Figure 3C). These data suggested that IL-15 was necessary to promote the activation and/or the recruitment of inflammatory monocytes. IL-15 did not induce the production of TNF-α and/or IL-1β in peritoneal macrophages from WT mice (naive or infected with T. gondii) (not shown). IL-15 also failed to stimulate the production of inflammatory cytokines by LP cells from naive WT mice even after stimulation by LPS or CD3 and CD28 antibodies (Figures S3F–3H). In contrast, the percentages as well as the absolute numbers of inflammatory monocytes, which increased on day 5 and even more on day 7 p.i. in infected WT mice (Figure 3D), were significantly reduced in Il15−/− mice, suggesting that IL-15 stimulates the recruitment of inflammatory monocytes (Figure 3E and data not shown). One attractive hypothesis to explain the role of IL-15 was the induction of chemokines able to stimulate intestinal migration of inflammatory monocytes. mRNA for such chemokines including CCL2, CCL3, CCL4, CCL5, and CXCL10 were markedly increased in intestinal biopsies and in isolated LP cells on day 7 p.i. compared to naive animals. The increase was comparable in WT and Il15−/− mice except for CCL3 mRNA, which were less induced in Il15−/− mice (Figures 4A, 4B , and S4A–S4C). Accordingly, CCL3 concentrations were significantly reduced in supernatants of LP cells from infected Il15−/−mice (Figure 4C). Confirming a role of CCL3 in inflammatory monocytes recruitment, treatment with a blocking CCL3 antibody significantly reduced the percentage of Ly6ChiF4/80+ LP cells (Figure 4D) and the production of TNF-α (Figure 4E). Anti-CCL3 treatment also reduced the severity of histological lesions (Figure 4F) but did not affect overall survival (Figure 4G). CCL3 binds two distinct receptors, CCR1 and CCR5, both of which can be expressed by inflammatory monocytes. On day 7 p.i., CCR5 mRNA were similarly increased in jejunal biopsies and in LP cells from WT and Il15−/− mice. In contrast, CCR1 mRNA was significantly lower in Il15−/− than in WT mice (Figure 4H). The role of CCR1 in the recruitment of inflammatory monocytes was therefore assessed with Ccr1−/− mice. Contrasting with their recruitment in infected WT mice, no increase in Ly6ChiF4/80+ LP cells nor in TNF-α+CD45+ LP cells was observed in Ccr1−/− mice during T. gondii infection and the percentage of such cells on day 7 were even lower than in Il15−/− mice (Figures 4I and 4J). Accordingly, IL-1β production by LP cells was abolished (Figure 4K). The small residual amounts of TNF-α may derive from neutrophils as indicated by the fact that these cells were normally recruited in the intestine of Ccr1−/− mice (Figure S4D) and produced small amounts of TNF-α when purified on day 7 (Figure S3E). As already described in Ccr1−/− mice (Khan et al., 2001Khan I.A. Murphy P.M. Casciotti L. Schwartzman J.D. Collins J. Gao J.L. Yeaman G.R. Mice lacking the chemokine receptor CCR1 show increased susceptibility to Toxoplasma gondii infection.J. Immunol. 2001; 166: 1930-1937Crossref PubMed Scopus (76) Google Scholar), intestinal lesions were less severe on day 7 p.i. than in WT mice (Figure 4L) but the mice died, probably because of 20- to 100-fold higher parasitic loads in MLN, spleen, and liver than WT mice (Figures S4E–S4G). Altogether these results indicated that the intestinal recruitment of Ly6ChiF4/80+ inflammatory monocytes during T. gondii-induced ileitis requires CCR1 and can be stimulated via CCL3. CCL3 can be produced by cells of hematopoietic or epithelial origin. CCL3 transcripts increased 100- to 200-fold more in LP cells than in enterocytes of infected mice (Figure 5A ). Analysis of LP subsets sorted on day 7 p.i. indicated that CCL3 mRNA was strongly upregulated in a subset of CD3−NKp46+NK1.1+ cells (Figure 5B). In these cells, upregulation of CCL3 RNA could already be detected at day 3 p.i., which is prior to CCR1+ inflammatory monocyte recruitment (Figure 5C). Murine LP contains two distinct lineages of NKp46+ innate lymphoid cells: IL-7-dependent Rorc+NKp46+NK1.1−CD127+ cells that produce IL-22 and NKp46+NK1.1+CD127− cells that depend on IL-15 and thus resembles classical splenic NK cells (reviewed in Colonna, 2009Colonna M. Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity.Immunity. 2009; 31: 15-23Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar, Spits and Di Santo, 2011Spits H. Di Santo J.P. The expanding family of innate lymphoid cells: regulators and effectors of immunity and tissue remodeling.Nat. Immunol. 2011; 12: 21-27Crossref PubMed Scopus (650) Google Scholar). Consistent with the hypothesis that LP NKp46+NK1.1+CD127− cells were the IL-15-dependent source of CCL3, their absolute number was significantly decreased in naive and infected Il15−/− mice compared to WT mice (Figure 5D) whereas the numbers of NKp46+NK1.1−CD127+ and of IL-22-containing NKp46+ cells were unchanged (Figures S5A and S5B). This hypothesis was confirmed by two complementary sets of experiments. First, by using hematopoietic chimeras, we observed that differentiation and/or homeostasis of LP CD3−NKp46+NK1.1+ cells required a stromal but not a hematopoietic source of IL-15 (Figures 5E and 5F). CCL3 mRNA, recruitment of LP Ly6ChiF4/80+ inflammatory monocytes, and ileitis severity were significantly reduced in irradiated Il15−/− mice reconstituted with WT bone marrow cells that lacked LP CD3−NKp46+NK1.1+ cells but not in irradiated WT reconstituted with Il15−/− bone marrow, which had normal percentages of LP CD3−NKp46+NK1.1+ cells (Figures 5G, 5H, and 1E). Second, treatment of mice with a depleting NK.1.1 antibody efficiently depleted LP NKp46+NK1.1+CD127− cells (Figures S5C and S5D) and simultaneously reduced CCL3 production by LP cells (Figure 5I). The percentage of LP Ly6ChiF4/80+ inflammatory monocytes and IL-1β and TNF-α mRNA were significantly decreased at day 7 p.i. and epithelial damage was attenuated (Figures 5J–5L). Altogether these data indicate that LP NKp46+NK1.1+CD127− cells depend on a stromal source of IL-15 for their differentiation and/or homeostasis and are an important source of CCL3 during T. gondii infection that contributes to CCR1+ inflammatory monocyte recruitment. Some CCL3 transcripts were also observed in inflammatory monocytes and neutrophils (Figure S5E). A major contribution of neutrophil-derived CCL3 for CCR1+ inflammatory monocytes recruitment seemed unlikely because these cells were observed only late in infection and were unaltered in the absence of IL-15 (Figure S5F). Moreover, their efficient depletion by Ly6G antibody did not reduce CCL3 production or CCR1+ inflammatory monocyte recruitment (Figures S5G–S5I). However, it remains possible that CCR1+ inflammatory monocyte-derived CCL3 observed late in infection might amplify their recruitment. In keeping with previous observations (Dorner et al., 2004Dorner B.G. Smith H.R. French A.R. Kim S. Poursine-Laurent J. Beckman D.L. Pingel J.T. Kroczek R.A. Yokoyama W.M. Coordinate expression of cytokines and chemokines by NK cells during murine cytomegalovirus infection.J. Immunol. 2004; 172: 3119-3131Crossref PubMed Scopus (104) Google Scholar, Fehniger et al., 1999Fehniger T.A. Shah M.H. Turner M.J. VanDeusen J.B. Whitman S.P. Cooper M.A. Suzuki K. Wechser M. Goodsaid F. Caligiuri M.A. Differential cytokine and chemokine gene expression by human NK cells following activation with IL-18 or IL-15 in combination with IL-12: implications for the innate immune response.J. Immunol. 1999; 162: 4511-4520PubMed Google Scholar), we found that CCL3 was induced in purified murine spleen NKp46+ cells by IL-15 and IL-18 and to a lesser extent by α-IFN but not by IFN-γ, IL-12, IL-21, or IL-23, nor by STAg that may stimulate NK cells (Figure 6A ; Sher et al., 1993Sher A. Oswald I.P. Hieny S. Gazzinelli R.T. Toxoplasma gondii induces a T-independent IFN-gamma response in natural killer cells that requires both adherent accessory cells and tumor necrosis factor-alpha.J. Immunol. 1993; 150: 3982-3989PubMed Google Scholar). A transient incr" @default.
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• W2009035135 title "Interleukin-15-Dependent NKp46+ Innate Lymphoid Cells Control Intestinal Inflammation by Recruiting Inflammatory Monocytes" @default.
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