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• W2000237582 abstract "Natural killer (NK) cells play a well-recognized role in early pathogen containment and in shaping acquired cell-mediated immunity. However, indirect evidence in humans and experimental models has suggested that NK cells also play negative regulatory roles during chronic disease. To formally test this hypothesis, we employed a well-defined experimental model of visceral leishmaniasis. Our data demonstrated that NKp46+CD49b+CD3− NK cells were recruited to the spleen and into hepatic granulomas, where they inhibited host protective immunity in an interleukin-10 (IL-10)-dependent manner. Although IL-10 mRNA could be detected in activated NK cells 24 hr after infection, the inhibitory function of NK cells was only acquired later during infection, coincident with increased IL-10 mRNA stability and an enhanced capacity to secrete IL-10 protein. Our data support a growing body of literature that implicates NK cells as negative regulators of cell-mediated immunity and suggest that NK cells, like CD4+ T helper 1 cells, may acquire immunoregulatory functions as a consequence of extensive activation. Natural killer (NK) cells play a well-recognized role in early pathogen containment and in shaping acquired cell-mediated immunity. However, indirect evidence in humans and experimental models has suggested that NK cells also play negative regulatory roles during chronic disease. To formally test this hypothesis, we employed a well-defined experimental model of visceral leishmaniasis. Our data demonstrated that NKp46+CD49b+CD3− NK cells were recruited to the spleen and into hepatic granulomas, where they inhibited host protective immunity in an interleukin-10 (IL-10)-dependent manner. Although IL-10 mRNA could be detected in activated NK cells 24 hr after infection, the inhibitory function of NK cells was only acquired later during infection, coincident with increased IL-10 mRNA stability and an enhanced capacity to secrete IL-10 protein. Our data support a growing body of literature that implicates NK cells as negative regulators of cell-mediated immunity and suggest that NK cells, like CD4+ T helper 1 cells, may acquire immunoregulatory functions as a consequence of extensive activation. Natural killer (NK) cells are known to provide a critical host defense system during the early phases of infection with a variety of viruses, fungi, bacteria, and parasites (Bancroft, 1993Bancroft G.J. The role of natural killer cells in innate resistance to infection.Curr. Opin. Immunol. 1993; 5: 503-510Crossref PubMed Scopus (279) Google Scholar, Biron et al., 1999Biron C.A. Nguyen K.B. Pien G.C. Cousens L.P. Salazar-Mather T.P. Natural killer cells in antiviral defense: function and regulation by innate cytokines.Annu. Rev. Immunol. 1999; 17: 189-220Crossref PubMed Scopus (1702) Google Scholar, Cerwenka and Lanier, 2001Cerwenka A. Lanier L.L. Natural killer cells, viruses and cancer.Nat. Rev. Immunol. 2001; 1: 41-49Crossref PubMed Scopus (669) Google Scholar, Farag et al., 2002Farag S.S. Fehniger T.A. Ruggeri L. Velardi A. Caligiuri M.A. Natural killer cell receptors: New biology and insights into the graft-versus-leukemia effect.Blood. 2002; 100: 1935-1947Crossref PubMed Scopus (411) Google Scholar, Smyth et al., 2002Smyth M.J. Hayakawa Y. Takeda K. Yagita H. New aspects of natural-killer-cell surveillance and therapy of cancer.Nat. Rev. Cancer. 2002; 2: 850-861Crossref PubMed Scopus (547) Google Scholar, Trinchieri, 1989Trinchieri G. Biology of natural killer cells.Adv. Immunol. 1989; 47: 187-376Crossref PubMed Scopus (2622) Google Scholar). NK cells do not possess conventional clonotypic antigen-specific receptors but are capable of spontaneously killing tumor cells and virus-infected cells that have downregulated one or more major histocompatibility complex (MHC) molecules and/or expressed certain stress antigens on their surface (Diefenbach and Raulet, 2003Diefenbach A. Raulet D.H. Innate immune recognition by stimulatory immunoreceptors.Curr. Opin. Immunol. 2003; 15: 37-44Crossref PubMed Scopus (78) Google Scholar, Mehrotra et al., 1998Mehrotra P.T. Donnelly R.P. Wong S. Kanegane H. Geremew A. Mostowski H.S. Furuke K. Siegel J.P. Bloom E.T. Production of IL-10 by human natural killer cells stimulated with IL-2 and/or IL-12.J. Immunol. 1998; 160: 2637-2644PubMed Google Scholar). NK cells have also been shown to play an important role during pregnancy (Moffett-King, 2002Moffett-King A. Natural killer cells and pregnancy.Nat. Rev. Immunol. 2002; 2: 656-663Crossref PubMed Scopus (925) Google Scholar), autoimmunity, and tissue inflammation (Homann et al., 2002Homann D. Jahreis A. Wolfe T. Hughes A. Coon B. van Stipdonk M.J. Prilliman K.R. Schoenberger S.P. von Herrath M.G. CD40L blockade prevents autoimmune diabetes by induction of bitypic NK/DC regulatory cells.Immunity. 2002; 16: 403-415Abstract Full Text Full Text PDF PubMed Scopus (142) Google Scholar, Shi et al., 2000Shi F.D. Wang H.B. Li H. Hong S. Taniguchi M. Link H. Van Kaer L. Ljunggren H.G. Natural killer cells determine the outcome of B cell-mediated autoimmunity.Nat. Immunol. 2000; 1: 245-251Crossref PubMed Scopus (153) Google Scholar). Target recognition and cytokine stimulation are the two major triggering mechanisms for NK cells, and both shape their effector responses (Alli and Khar, 2004Alli R.S. Khar A. Interleukin-12 secreted by mature dendritic cells mediates activation of NK cell function.FEBS Lett. 2004; 559: 71-76Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, Chakir et al., 2001Chakir H. Lemay A.M. Webb J.R. Cytokine expression by murine DX5+ cells in response to IL-12, IL-18, or the combination of IL-12 and IL-18.Cell. Immunol. 2001; 212: 71-81Crossref PubMed Scopus (24) 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, Lauwerys et al., 2000Lauwerys B.R. Garot N. Renauld J.C. Houssiau F.A. Cytokine production and killer activity of NK/T-NK cells derived with IL-2, IL-15, or the combination of IL-12 and IL-18.J. Immunol. 2000; 165: 1847-1853PubMed Scopus (174) Google Scholar, Mehrotra et al., 1998Mehrotra P.T. Donnelly R.P. Wong S. Kanegane H. Geremew A. Mostowski H.S. Furuke K. Siegel J.P. Bloom E.T. Production of IL-10 by human natural killer cells stimulated with IL-2 and/or IL-12.J. Immunol. 1998; 160: 2637-2644PubMed Google Scholar). Considerable advances have been made in understanding the receptors that activate and inhibit functionally mature NK cells and in the cytokines leading to IFN-γ production and cytoloytic activity. However, less is known about the regulation of other aspects of NK cell differentiation. In vitro studies have suggested that NK cells can also differentiate to produce interleukin-10 (IL-10) (Bodas et al., 2006Bodas M. Jain N. Awasthi A. Martin S. Penke Loka R.K. Dandekar D. Mitra D. Saha B. Inhibition of IL-2 induced IL-10 production as a principle of phase-specific immunotherapy.J. Immunol. 2006; 177: 4636-4643PubMed Google Scholar, Grant et al., 2008Grant L.R. Yao Z.-J. Hedrich C.M. Wang F. Moorthy A. Wilson K. Ranatunga D. Bream J.H. Stat-4-dependent, T-bet-independent regulation of IL-10 in NK cells.Genes Immun. 2008; 9: 316-327Crossref PubMed Scopus (58) Google Scholar, Moretta et al., 2002Moretta L. Biassoni R. Bottino C. Cantoni C. Pende D. Mingari M.C. Moretta A. Human NK cells and their receptors.Microbes Infect. 2002; 4: 1539-1544Crossref PubMed Scopus (56) Google Scholar) and may have regulatory activity (Deniz et al., 2008Deniz G. Erten G. Kucuksezer U.C. Kocacik D. Karagiannidis C. Aktas E. Akdis C.A. Akdis M. Regulatory NK cells suppress antigen-specific T cell responses.J. Immunol. 2008; 180: 850-857PubMed Google Scholar). Although a negative regulatory role for NK cells mediated through IL-10 has been suggested during tumor development, in pregnancy, and most recently during persistent Hepatitis C virus infection (Barber et al., 2007Barber M.A. Zhang T. Gagne B.A. Sentman C.L. NK cells negatively regulate antigen presentation and tumor-specific CTLs in a syngeneic lymphoma model.J. Immunol. 2007; 178: 6140-6147PubMed Google Scholar, De Maria et al., 2007De Maria A. Fogli M. Mazza S. Basso M. Picciotto A. Costa P. Congia S. Mingari M.C. Moretta L. Increased natural cytotoxicity receptor expression and relevant IL-10 production in NK cells from chronically infected viremic HCV patients.Eur. J. Immunol. 2007; 37: 445-455Crossref PubMed Scopus (167) Google Scholar, Vigano et al., 2001Vigano P. Gaffuri B. Somigliana E. Infantino M. Vignali M. Di Blasio A.M. Interleukin-10 is produced by human uterine natural killer cells but does not affect their production of interferon-gamma.Mol. Hum. Reprod. 2001; 7: 971-977Crossref PubMed Google Scholar), direct experimental evidence for a negative regulatory role of NK cells during infectious disease is lacking. We have been investigating the underlying cellular events that regulate the effectiveness of host protective immunity after infection with the protozoan parasite Leishmania donovani. Resistance to this pathogen operates largely through the development of granulomatous inflammation, positively regulated by both T helper 1 (Th1) and Th2 cell cytokines (Stager et al., 2003Stager S. Alexander J. Carter K.C. Brombacher F. Kaye P.M. Both interleukin-4 (IL-4) and IL-4 receptor alpha signaling contribute to the development of hepatic granulomas with optimal antileishmanial activity.Infect. Immun. 2003; 71: 4804-4807Crossref PubMed Scopus (106) Google Scholar) and negatively regulated largely by IL-10 (Murray et al., 2002Murray H.W. Lu C.M. Mauze S. Freeman S. Moreira A.L. Kaplan G. Coffman R.L. Interleukin-10 (IL-10) in experimental visceral leishmaniasis and IL-10 receptor blockade as immunotherapy.Infect. Immun. 2002; 70: 6284-6293Crossref PubMed Scopus (187) Google Scholar). Although natural T regulatory (Treg) cells have received much attention in models of cutaneous leishmaniasis caused by L. major (Belkaid et al., 2002Belkaid Y. Piccirillo C.A. Mendez S. Shevach E.M. Sacks D.L. CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity.Nature. 2002; 420: 502-507Crossref PubMed Scopus (1372) Google Scholar), in experimental visceral leishmaniasis (VL) caused by L. donovani (Stager et al., 2006Stager S. Maroof A. Zubairi S. Sanos S.L. Kopf M. Kaye P.M. Distinct roles for IL-6 and IL-12p40 in mediating protection against Leishmania donovani and the expansion of IL-10+ CD4+ T cells.Eur. J. Immunol. 2006; 36: 1764-1771Crossref PubMed Scopus (92) Google Scholar), chronic cutaneous leishmaniasis caused by L. major Seidman (Anderson et al., 2007Anderson C.F. Oukka M. Kuchroo V.J. Sacks D. CD4(+)CD25(-)Foxp3(-) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis.J. Exp. Med. 2007; 204: 285-297Crossref PubMed Scopus (436) Google Scholar), and also during human kala azar (Nylen et al., 2007Nylen S. Maurya R. Eidsmo L. Manandhar K.D. Sundar S. Sacks D. Splenic accumulation of IL-10 mRNA in T cells distinct from CD4+CD25+ (Foxp3) regulatory T cells in human visceral leishmaniasis.J. Exp. Med. 2007; 204: 805-817Crossref PubMed Scopus (248) Google Scholar), the bulk of IL-10-producing CD4+ T cells are inducible Foxp3− and CD25− regulatory T cells . A large fraction of these IL-10+ CD4+ T cells also coexpress IFN-γ, suggesting that they may, as in chronic toxoplasmosis (Jankovic et al., 2007Jankovic D. Kullberg M.C. Feng C.G. Goldszmid R.S. Collazo C.M. Wilson M. Wynn T.A. Kamanaka M. Flavell R.A. Sher A. Conventional T-bet(+)Foxp3(-) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection.J. Exp. Med. 2007; 204: 273-283Crossref PubMed Scopus (455) Google Scholar), represent a further stage of Th1 cell differentiation (O'Garra and Vieira, 2007O'Garra A. Vieira P. T(H)1 cells control themselves by producing interleukin-10.Nat. Rev. Immunol. 2007; 7: 425-428Crossref PubMed Scopus (447) Google Scholar). We now show that after L. donovani infection, NK cells accumulate in the spleen and in hepatic granulomas of infected mice and that these NK cells represent another source of IL-10 during infection. Using adoptive transfer, we also provide formal evidence that NK cells from infected mice suppressed host resistance in an IL-10-dependent manner. Although upregulation of IL-10 gene expression was also found to be a feature of early NK cell activation, only NK cells isolated from mice with established infection could suppress host resistance, a function associated with the acquisition of increased IL-10 mRNA stability and an enhancement of IL-10 protein secretion. Thus, our data suggest a mechanism whereby prolonged in vivo activation gives rise to a population of NK cells with altered posttranscriptional regulation of IL-10 gene expression, heightened capacity for IL-10 protein production, and inhibitory function. IL-10 is a major contributor to disease progression in many diseases (Murphy et al., 2001Murphy M.L. Wille U. Villegas E.N. Hunter C.A. Farrell J.P. IL-10 mediates susceptibility to Leishmania donovani infection.Eur. J. Immunol. 2001; 31: 2848-2856Crossref PubMed Scopus (210) Google Scholar, Murray et al., 2002Murray H.W. Lu C.M. Mauze S. Freeman S. Moreira A.L. Kaplan G. Coffman R.L. Interleukin-10 (IL-10) in experimental visceral leishmaniasis and IL-10 receptor blockade as immunotherapy.Infect. Immun. 2002; 70: 6284-6293Crossref PubMed Scopus (187) Google Scholar, Sharma et al., 1999Sharma S. Stolina M. Lin Y. Gardner B. Miller P.W. Kronenberg M. Dubinett S.M. T cell-derived IL-10 promotes lung cancer growth by suppressing both T cell and APC function.J. Immunol. 1999; 163: 5020-5028PubMed Google Scholar), and IL-10 production in experimental leishmaniasis has been attributed to CD4+ T cells and macrophages (Anderson et al., 2007Anderson C.F. Oukka M. Kuchroo V.J. Sacks D. CD4(+)CD25(-)Foxp3(-) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis.J. Exp. Med. 2007; 204: 285-297Crossref PubMed Scopus (436) Google Scholar, Miles et al., 2005Miles S.A. Conrad S.M. Alves R.G. Jeronimo S.M. Mosser D.M. A role for IgG immune complexes during infection with the intracellular pathogen Leishmania.J. Exp. Med. 2005; 201: 747-754Crossref PubMed Scopus (203) Google Scholar, Stager et al., 2006Stager S. Maroof A. Zubairi S. Sanos S.L. Kopf M. Kaye P.M. Distinct roles for IL-6 and IL-12p40 in mediating protection against Leishmania donovani and the expansion of IL-10+ CD4+ T cells.Eur. J. Immunol. 2006; 36: 1764-1771Crossref PubMed Scopus (92) Google Scholar). As part of a more complete analysis of the IL-10 response to L. donovani infection, we examined IL-10 mRNA accumulation in a variety of highly enriched (>98% pure) cell populations in the absence of in vitro restimulation. In accord with our recent description of the late emergence of IL-10-producing CD25−Foxp3− CD4+ T cells (Stager et al., 2006Stager S. Maroof A. Zubairi S. Sanos S.L. Kopf M. Kaye P.M. Distinct roles for IL-6 and IL-12p40 in mediating protection against Leishmania donovani and the expansion of IL-10+ CD4+ T cells.Eur. J. Immunol. 2006; 36: 1764-1771Crossref PubMed Scopus (92) Google Scholar), the accumulation of IL-10 mRNA within the splenic CD4+ T cell population increased over time. However, we were surprised to note that CD49b+ (DX5+) NK cells, and not CD4+ or CD8+ T cells, B cells, CD11chi cells, or macrophages, had accumulated most IL-10 mRNA by day 14 and that their mRNA accumulation equaled that of CD4+ T cells at day 28 after infection (p.i.; Figure 1A). Thus, within the splenic populations examined here, NK cells represented a previously unrecognized potential source of IL-10 during this infection. During L. donovani infection, the spleen undergoes extensive architectural remodeling associated with splenomegaly, both characteristics also associated with human disease (Kaye et al., 2004Kaye P.M. Svensson M. Ato M. Maroof A. Polley R. Stager S. Zubairi S. Engwerda C.R. The immunopathology of experimental visceral leishmaniasis.Immunol. Rev. 2004; 201: 239-253Crossref PubMed Scopus (165) Google Scholar). However, neither the number of NK cells nor their distribution has previously been reported. The latter has been problematic because of the lack of appropriate means to unambiguously identify NK cells in tissue sections in BALB/c mice. NKp46 has recently been described as a marker for NK cells in the mouse (Walzer et al., 2007Walzer T. Blery M. Chaix J. Fuseri N. Chasson L. Robbins S.H. Jaeger S. Andre P. Gauthier L. Daniel L. et al.Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46.Proc. Natl. Acad. Sci. USA. 2007; 104: 3384-3389Crossref PubMed Scopus (329) Google Scholar) and is suitable for in situ detection of NK cells via immunohistochemistry. First, we confirmed expression of NKp46 on CD49b+ splenic NK cells in naive BALB/c mice. As shown in Figure 1B (upper panel), more than 95% of CD3−CD49b+ cells stained brightly for NKp46. Using NKp46, we therefore determined the distribution of NK cells in the spleen of naive mice (Figure 1C). As suggested by previous studies (Andrews et al., 2001Andrews D.M. Farrell H.E. Densley E.H. Scalzo A.A. Shellam G.R. Degli-Esposti M.A. NK1.1+ cells and murine cytomegalovirus infection: what happens in situ?.J. Immunol. 2001; 166: 1796-1802PubMed Google Scholar, Dokun et al., 2001Dokun A.O. Chu D.T. Yang L. Bendelac A.S. Yokoyama W.M. Analysis of in situ NK cell responses during viral infection.J. Immunol. 2001; 167: 5286-5293PubMed Google Scholar, Walzer et al., 2007Walzer T. Blery M. Chaix J. Fuseri N. Chasson L. Robbins S.H. Jaeger S. Andre P. Gauthier L. Daniel L. et al.Identification, activation, and selective in vivo ablation of mouse NK cells via NKp46.Proc. Natl. Acad. Sci. USA. 2007; 104: 3384-3389Crossref PubMed Scopus (329) Google Scholar), NKp46+ cells were located predominantly within the marginal zone and red pulp. As with CD49b+ cells found in naive mice, almost all CD49b+ NK cells in L. donovani-infected mice coexpressed NKp46 (Figure 1B, lower panel). In addition, of CD3−CD49b+CD122+ cells, 95.5% ± 1.03% expressed NKp46 (compared to 97.4% ± 1.38% in naive mice; Figure S1 available online). In infected mice, a subset of CD49b+ cells also expressed CD11c at low intensity, potentially allowing their misclassification as immature conventional (cDCs) or plasmacytoid DCs (Blasius et al., 2007Blasius A.L. Barchet W. Cella M. Colonna M. Development and function of murine B220+CD11c+NK1.1+ cells identify them as a subset of NK cells.J. Exp. Med. 2007; 204: 2561-2568Crossref PubMed Scopus (133) Google Scholar, Caminschi et al., 2007Caminschi I. Ahmet F. Heger K. Brady J. Nutt S.L. Vremec D. Pietersz S. Lahoud M.H. Schofield L. Hansen D.S. et al.Putative IKDCs are functionally and developmentally similar to natural killer cells, but not to dendritic cells.J. Exp. Med. 2007; 204: 2579-2590Crossref PubMed Scopus (102) Google Scholar, Vosshenrich et al., 2007Vosshenrich C.A. Lesjean-Pottier S. Hasan M. Richard-Le Goff O. Corcuff E. Mandelboim O. Di Santo J.P. CD11cloB220+ interferon-producing killer dendritic cells are activated natural killer cells.J. Exp. Med. 2007; 204: 2569-2578Crossref PubMed Scopus (127) Google Scholar). However, the CD11cloCD49b+ cells observed in infected mice were uniformly MHCII− by flow cytometry, lacked intracellular MHCII by immunocytochemistry, did not express the costimulatory markers CD80 and CD86, and did not express either Gr-1 or B220 (Figures S2–S4 and data not shown). Staining with NKp46 therefore allowed us to unambiguously define NK cells in the spleen of mice infected with L. donovani (Figure 1D). NK cells were located within the red pulp and marginal zone, in a similar distribution to that of NK cells in naive mice. In the liver of infected mice, immunity to L. donovani is expressed in granulomas (Engwerda and Kaye, 2000Engwerda C.R. Kaye P.M. Organ-specific immune responses associated with infectious disease.Immunol. Today. 2000; 21: 73-78Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar). To determine whether NK cells contributed to the cellular composition of hepatic granulomas, we first confirmed NKp46 expression on hepatic CD49b+CD3− cells in both naive and infected mice (Figure 1E). Next, we performed immunohistochemistry with NKp46. The response of BALB/c mice has been well characterized previously and at day 14–28 p.i., granulomas can be seen in a variety of stages of maturation (Stager et al., 2003Stager S. Alexander J. Carter K.C. Brombacher F. Kaye P.M. Both interleukin-4 (IL-4) and IL-4 receptor alpha signaling contribute to the development of hepatic granulomas with optimal antileishmanial activity.Infect. Immun. 2003; 71: 4804-4807Crossref PubMed Scopus (106) Google Scholar). NKp46+CD3− cells were readily identified within immature and mature granulomas and also within the parenchyma (Figures 1F–1H). By thin-section analysis, ∼75% of all detectable hepatic NK cells were within granulomas, and NK cells were observed in ∼60% of the granulomas examined. Given the relatively low frequency of NK cells per granuloma, we cannot rule out the possibility that all granulomas might contain NK cells if examined across their entire volume. To determine whether splenic and hepatic NK cells increased in number during infection, we quantified NK cells by flow cytometry. As shown in Figure 2A, in mice infected with L. donovani, the absolute number of splenic NK cells increased by 3-fold. A similar, though less pronounced, increase in hepatic NK cells was also observed (Figure 2B). To confirm the kinetics of acquisition of IL-10 mRNA by hepatic CD49b+NKp46+ NK cells in relation to CD4+ and CD8+ T cells, we again performed qRT-PCR on flow-sorted cells at different times after infection. As shown in Figures 2C and 2D, both splenic and hepatic NK cells with increased IL-10 mRNA accumulation were readily detected by day 7 p.i. Hepatic CD4+ T cells with elevated levels of IL-10 mRNA appeared more rapidly than in spleen, whereas the kinetics of the IL-10 response in CD8+ T cells was similar in both organs. Together, these data demonstrate that during the course of L. donovani infection, NK cells are one of the first populations to increase their potential for IL-10 production, that their numbers increase in infected tissues, and that they can home specifically into both the infected spleen and sites of granulomatous inflammation. Next, we wished to determine whether NK cells had the capacity to regulate the outcome of infection, as might be suggested by their increased accumulation of IL-10 mRNA. We first depleted NK cells in vivo by using anti-ASGM1. Treatment of mice with anti-ASGM1 has been commonly used to deplete NK cells, though this antibody has known reactivity against other cells as well (Slifka et al., 2000Slifka M.K. Pagarigan R.R. Whitton J.L. NK markers are expressed on a high percentage of virus-specific CD8+ and CD4+ T cells.J. Immunol. 2000; 164: 2009-2015PubMed Google Scholar). Antibodies were administered over the first 6 days of infection (see Experimental Procedures) and led to a rapid decrease in the frequency of CD49b+ cells (from 2.27% in control-treated mice to 0.04% in mice treated for 24 hr with anti-ASGM1), which was sustained over the first 7 days p.i. Treatment with anti-ASGMI significantly reduced parasite burden in the spleen (to 55% ± 8.5% of control; p < 0.001) and liver (to 48% ± 9% of control; p < 0.001) of infected mice, as measured at day 28 p.i. Whereas ASGM1 stained < 2% of CD4+ and < 5% of CD8+ spleen cells in naive BALB/c mice, ASGM1 expression was markedly increased on T cells in infected mice (∼15% and ∼32% of CD4+ and CD8+ T cells, respectively, at day 21 p.i.; data not shown), making this approach unsuitable for analyzing the role of NK cells at later stages of infection. To circumvent this problem, we used an adoptive-transfer approach to test whether NK cells could influence the outcome of infection in otherwise unmanipulated hosts. Recipient BALB/c mice were infected with L. donovani, and at day 21 p.i. they were adoptively transferred with 106 NK cells derived from either naive or day 21-infected mice. Parasite burden was then evaluated 7 days later (day 28 p.i.). At this time, hepatic resistance was beginning to be expressed, whereas parasite numbers were increasing in the spleen (Engwerda and Kaye, 2000Engwerda C.R. Kaye P.M. Organ-specific immune responses associated with infectious disease.Immunol. Today. 2000; 21: 73-78Abstract Full Text Full Text PDF PubMed Scopus (132) Google Scholar). Transfer of NK cells isolated from the spleen of naive mice into animals that had been previously infected for 21 days had no effect on splenic (Figure 3A) or hepatic (Figure 3B) parasite burden. In contrast, adoptive transfer of splenic NK cells from day 21-infected mice into day 21-infected recipients significantly suppressed host resistance in both organs. In four independent experiments (n = 13–18 mice), NK cells from day 21-infected mice increased parasite burden by 2.47 ± 0.17-fold and 1.86 ± 0.16-fold in spleen and liver respectively (p < 0.001), whereas NK cells from naive mice increased parasite burden by 1.1 ± 0.16-fold and 1.25 ± 0.02-fold in spleen and liver, respectively (p = ns). These data indicated that NK cells from infected but not naive mice could inhibit host resistance to L. donovani. To confirm the fate of the adoptively transferred NK cells, we CFSE labeled NK cells from naive and infected mice prior to transfer, in order to allow visualization by immunohistochemistry and flow cytometry. Transferred NK cells could be detected in the spleen (Figures 3C and 3D), with a localization similar to that seen for endogenous NK cells (Figure 1D). By flow cytometry, the number of recovered NK cells was similar at 18 hr and 7 days after transfer (Figure 3E). These data suggest that the differences in suppressive function of NK cells from naive and infected mice were not due to differential survival or homing. Using this approach, we also confirmed that NK cells directly home into hepatic granulomas (Figures 3F and 3G). As with endogenous NK cells, transferred NK cells were observed in most, but not all, granulomas (Figure 3F). As ∼50% of NK cells in infected BALB/c mice expressed CD11c (Figure S2), we wished to determine whether this inhibitory function might be attributable to this emergent CD11clo population of NK cells. However, as shown in Figures 3H and 3I, sorted CD11− and CD11clo subsets of CD49b+ NK cells equally inhibited host resistance (by 3.05 ± 0.5-fold and 3.41 ± 0.56-fold in the spleen and 2.59 ± 0.25-fold and 3.22 ± 0.24-fold in the liver for CD11c− and CD11lo NK cells, respectively; n = 5 and p < 0.01 in all cases versus no transfer or transfer of naive NK cells). In spite of this inhibitory activity, both CD11− and CD11clo subsets also exhibited enhanced cytotoxic effector function compared to NK cells from naive mice (Figure S5). By these assays, diverse functions of NK cells did not, therefore, segregate on the basis of CD11c expression. Although providing the first functional evidence that NK cells can suppress host resistance, these experiments did not directly address whether this was mediated via IL-10. To address this question, we developed a mixed-chimera approach, which allowed both progression of L. donovani infection and also the activation of both IL-10-sufficient and IL-10-deficient NK cells within the same infected host. We first generated mixed chimeras on the BALB background, transferring bone marrow derived from Thy1.2+ BALB.Il10−/− and Thy1.1+ BALB.Il10+/+ into Thy1.1+ BALB.Il10+/+ recipients. However, as a result of limited expression of Thy1 on NK cells (Dunn and North, 1991Dunn P.L. North R.J. Resolution of primary murine listeriosis and acquired resistance to lethal secondary infection can be mediated predominantly by Thy-1+ CD4- CD8- cells.J. Infect. Dis. 1991; 164: 869-877Crossref PubMed Scopus (59) Google Scholar, Rahal et al., 1991Rahal M.D. Koo G.C. Osmond D.G. Population dynamics of “null” and Thy1lo lymphocytes in mouse bone marrow: genesis of cells with natural killer cell lineage characteristics.Cell. Immunol. 1991; 134: 111-125Crossref PubMed Scopus (10) Google Scholar), it was not possible to recover sufficient Il10−/− and Il10+/+ NK cells for subsequent adoptive transfer. We therefore used CD45.1+ B6.Il10+/+ and CD45.2+ B10.Il10−/− mice as an alternate genetic system. As in BALB/c mice, the number of CD3−NKp46+ NK cells in the spleen of infected B6 mice also increased during infection (from 2.7 ± 0.2 to 3.9 ± 1.5 × 106 per spleen), and these NK cells had increased accumulation of IL-10 mRNA compared to naive mice (8.4 ± 0.3-fold). However, the magnitude of the NK response in B6 mice, as measured by both these parameters, was clearly more muted than in BALB/c mice (Figure 1, Figure 2). Nevertheless, we generated (CD45.1+ B6.Il10+/+ + CD45.2+ B10.Il10−/−) → CD45.1 B6.Il10+/+ irradiation chimeras and after 8 weeks of reconstitution, these mice were infected with L. donovani (Figure 4A). At day 28 p.i., IL-10-sufficient (CD49b+CD45.1+) and IL-10-deficient (CD49b+ CD45.2+) NK cells (Figure 4B) were present in similar ratios. Sorted (>98% purity) NK cells were then transferred into day 21-infected CD45.1+ B6.Il10+/+ recipient mice. Whereas IL-10-sufficent NK cells inhibited splenic (Figure 4C) and hepatic (Figure 4D) resistance to L. donovani, the transfer of Il10−/− NK cells had n" @default.
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• W2000237582 title "Posttranscriptional Regulation of Il10 Gene Expression Allows Natural Killer Cells to Express Immunoregulatory Function" @default.
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