Role of CC Chemokine Receptor 4 in Natural Killer Cell Activation during Acute Cigarette Smoke Exposure

Cigarette smoke (CS)–induced lung injury involves innate immune responses. The activation of innate effector cells is thought to require cross talk with dendritic cells (DCs) and macrophages, but the mediators of interaction are unknown. One candidate, CC chemokine receptor 4 (CCR4), is expressed by innate and adaptive effector cells, and its ligands are produced by DCs and macrophages. Using flow cytometry and confocal microscopy, we defined innate responses of lung myeloid DCs, macrophages, and conventional natural killer (NK) cells in mice exposed to CS over 4 days and examined the contribution of CCR4 using CCR4 knockout (CCR4−/−) mice. CS affected populations differently, causing an increase in F4/80+ macrophages, a reduction in parenchymal CD11c+CD11b+CD103− DCs, but no effect on mucosal CD11c+CD11b−CD103+ DCs. CS also induced a population of primed/activated CD69+ NK cells and bronchoepithelial expression of the stress-related NKG2D receptor–activating protein, retinoic acid early transcript 1. CS-exposed CCR4−/− mice were similar to controls regarding effects on DCs and macrophages but displayed substantially impaired NK priming/activation and reduced expression of transcripts for interferon gamma, CXCL10, and retinoic acid early transcript 1. Quantitative confocal microscopy revealed that lungs of CS-exposed CCR4−/− mice had significantly reduced contacts of NK cells with CD11c+ cells. These findings demonstrate that acute CS exposure elicits NK cell responses and suggest that CCR4 promotes NK cell priming/activation by mediating contacts with sentinel cells in the lung. Cigarette smoke (CS)–induced lung injury involves innate immune responses. The activation of innate effector cells is thought to require cross talk with dendritic cells (DCs) and macrophages, but the mediators of interaction are unknown. One candidate, CC chemokine receptor 4 (CCR4), is expressed by innate and adaptive effector cells, and its ligands are produced by DCs and macrophages. Using flow cytometry and confocal microscopy, we defined innate responses of lung myeloid DCs, macrophages, and conventional natural killer (NK) cells in mice exposed to CS over 4 days and examined the contribution of CCR4 using CCR4 knockout (CCR4−/−) mice. CS affected populations differently, causing an increase in F4/80+ macrophages, a reduction in parenchymal CD11c+CD11b+CD103− DCs, but no effect on mucosal CD11c+CD11b−CD103+ DCs. CS also induced a population of primed/activated CD69+ NK cells and bronchoepithelial expression of the stress-related NKG2D receptor–activating protein, retinoic acid early transcript 1. CS-exposed CCR4−/− mice were similar to controls regarding effects on DCs and macrophages but displayed substantially impaired NK priming/activation and reduced expression of transcripts for interferon gamma, CXCL10, and retinoic acid early transcript 1. Quantitative confocal microscopy revealed that lungs of CS-exposed CCR4−/− mice had significantly reduced contacts of NK cells with CD11c+ cells. These findings demonstrate that acute CS exposure elicits NK cell responses and suggest that CCR4 promotes NK cell priming/activation by mediating contacts with sentinel cells in the lung. In recent years, the relationship between cigarette smoke (CS) and immunity has been subject to extensive investigation. Tobacco abuse can be viewed as a model of repeated lung injury with superimposed toxic and pharmacologic effects that elicit and modify pulmonary immune responses. Various studies suggest that CS-related chronic inflammatory conditions, such as chronic obstructive pulmonary disease, involve innate and adaptive immune responses, but much controversy remains as to how chronic lung injury is established and sustained.1Hogg J.C. Timens W. The pathology of chronic obstructive pulmonary disease.Annu Rev Pathol. 2009; 4: 435-459Crossref PubMed Scopus (502) Google Scholar Innate immunity in the lung is mediated by multiple elements, including the mucociliary system, epithelial-derived defensins, phagocytic leukocytes, dendritic cells (DCs), and lymphoid populations, such as conventional natural killer (NK) cells, NK T cells, and γ/δ T cells. Initiation of innate immune responses involves cell receptors that recognize microbial- or damage-associated molecular patterns. In particular, sentinel cells, such as DCs and macrophages, are pivotal not only in innate recognition but also in regulating immune responses through interactions with effector cells, such as NK cells.2Cooper M.A. Fehniger T.A. Fuchs A. Colonna M. Caligiuri M.A. NK cell and DC interactions.Trends Immunol. 2004; 25: 47-52Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar Conventional NK cells, traditionally considered innate responders, represent an important component of the pulmonary immune response, mounting rapid and potent responses to infection, injury, and neoplasms. However, NK cells are now known to participate as innate and memory effectors possibly contributing to chronic inflammation.3Sun J.C. Lopez-Verges S. Kim C.C. DeRisi J.L. Lanier L.L. NK cells and immune “memory.”.J Immunol. 2011; 186: 1891-1897Crossref PubMed Scopus (163) Google Scholar Moreover, long-term CS exposure has been demonstrated to prime NK cells, which may promote chronic lung epithelial cell injury,4Motz G.T. Eppert B.L. Wortham B.W. Amos-Kroohs R.M. Flury J.L. Wesselkamper S.C. Borchers M.T. Chronic cigarette smoke exposure primes NK cell activation in a mouse model of chronic obstructive pulmonary disease.J Immunol. 2010; 184: 4460-4469Crossref PubMed Scopus (65) Google Scholar but the mechanisms of NK cell maturation, priming, and activation are not fully understood. In a model of pulmonary mycobacterial infection, we recently demonstrated that CC chemokine receptor 4 (CCR4) and its ligands contributed to early innate resistance to infection, which was related to NK cell activation.5Stolberg V.R. Chiu B.C. Schmidt B.M. Kunkel S.L. Sandor M. Chensue S.W. CC chemokine receptor 4 contributes to innate NK and chronic stage T helper cell recall responses during Mycobacterium bovis infection.Am J Pathol. 2011; 178: 233-244Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar CCR4 is reportedly expressed in a variety of effector cell populations, including memory T cells, regulatory T cells, and NK cells.6Berahovich R.D. Lai N.L. Wei Z. Lanier L.L. Schall T.J. Evidence for NK cell subsets based on chemokine receptor expression.J Immunol. 2006; 177: 7833-7840PubMed Google Scholar, 7Campbell J.J. O’Connell D.J. Wurbel M.A. Cutting Edge: chemokine receptor CCR4 is necessary for antigen-driven cutaneous accumulation of CD4 T cells under physiological conditions.J Immunol. 2007; 178: 3358-3362Crossref PubMed Scopus (93) Google Scholar, 8Iellem A. Mariani M. Lang R. Recalde H. Panina-Bordignon P. Sinigaglia F. D’Ambrosio D. Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells.J Exp Med. 2001; 194: 847-853Crossref PubMed Scopus (747) Google Scholar, 9Maghazachi A.A. G protein-coupled receptors in natural killer cells.J Leukoc Biol. 2003; 74: 16-24Crossref PubMed Scopus (66) Google Scholar, 10Sallusto F. Lenig D. Mackay C.R. Lanzavecchia A. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes.J Exp Med. 1998; 187: 875-883Crossref PubMed Scopus (1378) Google Scholar Ligands of CCR4 have been reported in animal models of CS exposure and in bronchoalveolar lavages of human smokers.11Ritter M. Goggel R. Chaudhary N. Wiedenmann A. Jung B. Weith A. Seither P. Elevated expression of TARC (CCL17) and MDC (CCL22) in models of cigarette smoke-induced pulmonary inflammation.Biochem Biophys Res Commun. 2005; 334: PubMed Scopus Google Scholar, S. M. CC chemokine receptor 4 by bronchoalveolar cells in acute Immunol. 2005; PubMed Scopus Google Scholar Moreover, DCs and macrophages are known of CCR4 The and activation of NK cells is thought to involve cross talk with sentinel cells, such as M. W. P. A. cells prime natural killer cells by 2007; Full Text Full Text PDF PubMed Scopus Google Scholar on we that CCR4 to the priming/activation of NK cells by contacts between effector and sentinel cells in the lung. Using flow and confocal we defined cell and NK cell responses acute CS exposure and the effect of CCR4 The findings a model in which CCR4 promotes contacts between sentinel and effector cells, a for rapid effector priming/activation that in the of CS exposure to chronic lung to and mice were The the CCR4 (CCR4−/−) were and were as and a A. S. P. R. F. for CC chemokine receptor 4 in Exp Med. PubMed Scopus Google Scholar was by using and were under specific and were with and in a on and of the studies were by the of on and of of with the was by a cigarette is to a of and were exposed on 4 days for 1 in a and exposure with an for in mouse with with a of were exposure and were in the for the of the were with for and the of during a exposure was were in an exposed to with no were on for and lungs were with of and in of were and for studies as lung for flow for confocal microscopy, and for transcript expression flow lung were in a on for and lung was were by for in of and of lungs were in of and were through a cell and by and were by and by flow were in 2 of with for were with of for were and were using of of for the lymphoid or the DC CCR4 were with with with were for and were with 2 of were through a flow flow and were for and were to 1 and a of for lymphoid or DC was as populations were a of a to 1 by and and was and with controls with were in the was to transcript lung were in of and were for lung was using the to the were using the to the The were for expression of CXCL10, and using was as the The was for using the for lung were with in and were rapid in mounting on were on and in were in for and were with of in for were and were a in specific and or and were for 1 in the or were in and were for in the were for with and mounting was for mounting was was using a confocal with a for and an of to and The were and using with the to or for and of defined of the were to of lung parenchymal a was with were to of of with a of were and the of the were DCs were defined as cells with cell and of CD11c+ and of or NK cells were and were to of of were not NK cell the of contacts between NK cells and and cells was and to NK cells. were to for was for with a of with was for of the innate response to a CS exposure we effects on DC and The lung populations of myeloid DCs with and R. and of dendritic 2010; PubMed Scopus Google Scholar is the for the which is expressed as a with The to the epithelial cell is with mucosal epithelial interactions and is thought to DC with or lung Using a of and populations can be by flow with the by F. lung epithelial dendritic cell population and Immunol. 2006; Google Scholar confocal microscopy demonstrated that cells with and of DCs were to and cells were in the parenchymal Using we examined the effect of CS exposure on and on lung CS substantially the of in CD11c+ cells of that was an in the of DCs but no effect on DCs and In macrophages by was by confocal which a in the of cells in the but no effect on populations and These studies demonstrated that CS exposure reduced lung parenchymal but not mucosal DCs. was that was to of or in flow of CS-exposed mice in with controls However, DC studies are for Conventional NK cells are a immune effector population in the of lymphoid killer cells in and of the 2009; PubMed Scopus Google Scholar of NK cells in human long-term have reported or impaired NK cell B. S. of on human natural killer cell PubMed Scopus Google Scholar However, recent suggest NK cell with in with chronic obstructive pulmonary activation of killer cells in the and the a of and chronic obstructive pulmonary PubMed Scopus Google Scholar In a recent of mouse lung NK cells, G.T. Eppert B.L. Wortham B.W. Amos-Kroohs R.M. Flury J.L. Wesselkamper S.C. Borchers M.T. Chronic cigarette smoke exposure primes NK cell activation in a mouse model of chronic obstructive pulmonary disease.J Immunol. 2010; 184: 4460-4469Crossref PubMed Scopus (65) Google Scholar reported that long-term CS exposure induced NK cell with activation on with or In of we examined lung NK cells as CS exposure and NK priming/activation by expression of the revealed a of lung NK cells in CS-exposed with mice with significantly of cells also confocal to and NK cells using which a of conventional NK cells is expressed by only a of NK T cells. In we the expression of retinoic acid early transcript 1 a for the receptor expressed by NK and T cells that promote NK cells were in parenchymal and mucosal of CS-exposed mice and In was in the of CS-exposed mice with The confocal the flow a NK cells in the lung with a increase in NK cells for was also and the a increase in transcript in CS-exposed mice of NK cells and expression in lungs of CS-exposed and mice. of CS-exposed and mice were and to with confocal for the of CS-exposed lung cells of CS-exposed lung cells expression in mucosal and of Quantitative confocal of cells in parenchymal and mucosal NK cells were in with of transcript in CS-exposed and and are These demonstrated that in to effects on and macrophages, CS exposure induced a response in and a population of primed/activated NK cells. reported that CCR4 was for NK cell activation during the response to Mycobacterium bovis V.R. Chiu B.C. Schmidt B.M. Kunkel S.L. Sandor M. Chensue S.W. CC chemokine receptor 4 contributes to innate NK and chronic stage T helper cell recall responses during Mycobacterium bovis infection.Am J Pathol. 2011; 178: 233-244Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar that CCR4 and its ligands also participate in the NK cell CCR4 is a of chemokine receptors expressed by of memory T cells and NK A.A. A. Schall T.J. the of NK and NK cells. for G Immunol. Google Scholar CCR4 we lung and lymphoid cells mice for conventional NK cells the population of cells These cells were also killer cell receptor with a not CCR4 was also in a of NK cells, but was lung NK cells, that NK cells were in the In with cells were memory but not T cells. The expression is in that CCR4 was also not significantly expressed by populations not the ligands for and are expressed by DCs and macrophages in including the a for The TARC is expressed by subsets of dendritic cells and T J Immunol. PubMed Google Scholar, F. B. Lenig D. M. S. R. R. M. Lanzavecchia A. and of chemokine dendritic cell J Immunol. PubMed Scopus Google Scholar, J.L. Quantitative of chemokine expression by dendritic cell subsets in and in Leukoc Biol. 2001; Google Scholar, and potent chemokine by lung dendritic cells in and in lung Immunol. 2007; 178: Google Scholar we transcript for and in lungs of and we no In with studies of lung and A. S. W. S. R. P. M. A. S. to of and mouse dendritic cells.J Leukoc Biol. PubMed Scopus Google Scholar confocal of lungs for revealed expression in CD11c+ cells in the parenchymal and established a for CCR4 and its ligands in the we the innate response in and CCR4−/− mice. was no of CCR4 on F4/80+ and DC populations in CS-exposed mice that receptor was not for lung or of cells. were also no in the of expression between and knockout mice However, as in CCR4 the NK cell and CCR4−/− CS-exposed mice had of lung NK cells with which also had NK cell populations not but CCR4−/− mice significantly impaired NK cell priming/activation as by was that the findings were to of NK cells in CCR4−/− mice. However, not be to and knockout (CCR4−/−) mice had and lymphoid populations in the CCR4 was in NK cell or activation in we transcript expression for a of and transcript as of CS-exposed with mice. CCR4−/− mice displayed reduced transcript of and the chemokine were no in CCR4 transcripts with were also no in the transcript for the NK and and However, was that knockout mice expression of transcripts and a reduction in transcripts for the NKG2D receptor–activating The CCR4 transcript knockout Quantitative confocal was to in NK cell were no between and CCR4−/− mice parenchymal populations, but CCR4−/− mice a reduction in cells that CCR4 was for of NK cells. The activation of NK cells involves a of of which is NK cell The is to the effect of that NK cells in a involves interaction of NK cells with or macrophages that the cell M. W. P. A. cells prime natural killer cells by 2007; Full Text Full Text PDF PubMed Scopus Google Scholar NK cells to but not effector such as or such as NKG2D are S.C. Eppert B.L. G.T. D.J. Borchers M.T. NKG2D is for NK cell activation in Immunol. Google Scholar on the we that CCR4 to NK cell in the lung by interactions with sentinel cells. Using confocal microscopy, we the of NK cells in with CD11c+ and cells in CS-exposed and CCR4−/− mice. of NK cell contacts with CD11c+ and cells in CS-exposed mice are and interactions were parenchymal and Moreover, contacts were as were multiple and were in parenchymal which may the that a of can be in In CS-exposed CCR4−/− contacts were and revealed an reduction in contacts in lungs of CCR4−/− mice innate effector cell responses are as to lung S. C.C. Innate immune are for cigarette smoke-induced in J Biol. 2010; PubMed Scopus Google Scholar The and of effector cells is thought to be mediated by but the of the of of be defined recently reported that CCR4 was for NK cell activation during innate stage of V.R. Chiu B.C. Schmidt B.M. Kunkel S.L. Sandor M. Chensue S.W. CC chemokine receptor 4 contributes to innate NK and chronic stage T helper cell recall responses during Mycobacterium bovis infection.Am J Pathol. 2011; 178: 233-244Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar CCR4 was to be to adaptive memory T cells, but studies demonstrated expression by a variety of effector populations, such as regulatory T cells, and NK cells.6Berahovich R.D. Lai N.L. Wei Z. Lanier L.L. Schall T.J. Evidence for NK cell subsets based on chemokine receptor expression.J Immunol. 2006; 177: 7833-7840PubMed Google Scholar, 7Campbell J.J. O’Connell D.J. Wurbel M.A. Cutting Edge: chemokine receptor CCR4 is necessary for antigen-driven cutaneous accumulation of CD4 T cells under physiological conditions.J Immunol. 2007; 178: 3358-3362Crossref PubMed Scopus (93) Google Scholar, 8Iellem A. Mariani M. Lang R. Recalde H. Panina-Bordignon P. Sinigaglia F. D’Ambrosio D. Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells.J Exp Med. 2001; 194: 847-853Crossref PubMed Scopus (747) Google Scholar, 9Maghazachi A.A. G protein-coupled receptors in natural killer cells.J Leukoc Biol. 2003; 74: 16-24Crossref PubMed Scopus (66) Google Scholar, 10Sallusto F. Lenig D. Mackay C.R. Lanzavecchia A. Flexible programs of chemokine receptor expression on human polarized T helper 1 and 2 lymphocytes.J Exp Med. 1998; 187: 875-883Crossref PubMed Scopus (1378) Google Scholar The chemokine ligands for CCR4 are produced by macrophages and under and conditions, a for in regulating effector cell through interactions with sentinel cells. the of CCR4 in innate responses in the we and NK cell responses in mouse lungs CS a adaptive responses are NK cell responses are by adaptive responses, but are in that can the of cross talk between DCs and NK cells is thought to the and activation of early M.A. Fehniger T.A. Fuchs A. Colonna M. Caligiuri M.A. NK cell and DC interactions.Trends Immunol. 2004; 25: 47-52Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar, R. M. M. The between human dendritic cells and natural killer cells.J Innate 2011; PubMed Scopus Google Scholar, M. killer cell in the of immune 2005; PubMed Scopus Google Scholar However, the and mediating cell interactions have to be fully studies the of CS effects on DC populations, we a flow to and which represent and sentinel DCs, CS exposure affected populations differently, causing a reduction in the parenchymal population but with no effect on the DCs. These of R. D. A.A. Cigarette smoke-induced accumulation of lung dendritic cells is in PubMed Scopus Google Scholar reported an accumulation of CS However, that the exposure of the may be to effects on The also examined and in which may have The of effects of CS exposure on parenchymal and mucosal DCs is and in or of the or injury, DCs to lymphoid and are was by the of in However, that we NK interactions that in DC as a of the reduction in D. S. and of dendritic cells by natural killer cells.J Exp Med. PubMed Scopus Google Scholar In known as DC NK cells in the of DCs that immune responses. of and has not been but populations are and DCs of have the to cell T cells, and are on expression for R.M. pulmonary dendritic cells and Exp Med. 2011; PubMed Scopus Google Scholar a may be to with in a reduction of the the findings in CS-exposed mice may of parenchymal and mucosal and studies are to The of was not is a in CS-exposed and H. Timens W. effects of cigarette smoke on and a 2004; PubMed Scopus Google Scholar In macrophages and are known of the CCR4 S. M. CC chemokine receptor 4 by bronchoalveolar cells in acute Immunol. 2005; PubMed Scopus Google Scholar However, CCR4 ligands and are reportedly of and potent chemokine by lung dendritic cells in and in lung Immunol. 2007; 178: Google Scholar, A. S. W. S. R. P. M. A. S. to of and mouse dendritic cells.J Leukoc Biol. PubMed Scopus Google Scholar, M. A. R. S. P. R. A. P. A. S. cells as a of in and in J Immunol. 2001; PubMed Scopus Google Scholar In with the confocal demonstrated expression in CD11c+ cells in lung and that were with DCs and possibly macrophages as effects on and populations, CS exposure a population of CD69+ NK cells. microscopy of lungs NK cells in the of CS-exposed and with the of a NK cell killer cells in and of the 2009; PubMed Scopus Google Scholar In to CS a increase in NK cells. Moreover, CS exposure also induced the NKG2D receptor–activating in similar to that reported in models of long-term CS M.T. Wesselkamper S.C. A. A. S.L. N.L. M. Eppert B.L. G.T. M. activation by pulmonary epithelial cells promotes the of disease.J 2009; PubMed Scopus Google Scholar NKG2D receptors are expressed by NK and T cells and promote In a recent NK cells CS-exposed mice displayed of NKG2D cells, and NKG2D mice had reduced lung injury in a model of of CS B.W. Eppert B.L. G.T. Flury J.L. M. M. S.W. Borchers M.T. NKG2D NK cell and in a mouse model of chronic obstructive pulmonary disease.J Immunol. PubMed Scopus Google Scholar These studies activation of NK cells by NKG2D as the of lung The are with and suggest a for CCR4 and its ligands in CCR4 not the of lung or macrophages CS However, we a of NK cell activation in CCR4−/− mice. The was with impaired of transcripts in CS-exposed which may reduced by NK cells as we demonstrated in lungs of CCR4−/− V.R. Chiu B.C. Schmidt B.M. Kunkel S.L. Sandor M. Chensue S.W. CC chemokine receptor 4 contributes to innate NK and chronic stage T helper cell recall responses during Mycobacterium bovis infection.Am J Pathol. 2011; 178: 233-244Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar was a of a to a response, and relationship of and is with the reported of lungs of CCR4−/− mice reduced that injury were One is that CCR4 knockout affected to promotes NKG2D expression in cells, to NK Z. Z. effects of and on the expression of in PubMed Scopus Google Scholar DCs are thought to be of not DCs in but CCR4−/− mice displayed a reduction in transcripts for the chemokine which is chemotactic for mouse NK cells and S. W. A. F. of dendritic cells in and Immunol. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar of NKG2D expression promote rapid of or epithelial cells, but studies be to NK cell cross talk with CD11c+ has been in the but the in and for interactions have been for the that such interactions can in the lung and to in on or The CCR4 was reported to be chemotactic for human NK cells its R. D. S. P. D. A. chemokine a for dendritic cells, and natural killer cells.J Exp Med. PubMed Scopus Google Scholar of NK cells were effector cell populations reported to A.A. A. Schall T.J. the of NK and NK cells. for G Immunol. Google Scholar findings by the of a population of NK cells in mouse in with we CCR4 expression in memory T cells. NK and memory T cells a receptor expressed by effector cells, which is also a for NK S.L. The and activation of by natural killer (NK) cells and its in the of 2004; PubMed Scopus Google Scholar CCR4 reportedly DC contacts with T cells in M. H. Cutting CCR4 T cell to dendritic cells.J Immunol. 2001; Google Scholar and the of in F. H. A. H. chemokine and CCR4 are in the of T cell in human and lymphoid J Pathol. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar receptor has also been in NK T cell of DCs, which promote P. W. through of Immunol. 2010; PubMed Scopus Google Scholar In of that DCs can NK M.A. Fehniger T.A. Fuchs A. Colonna M. Caligiuri M.A. NK cell and DC interactions.Trends Immunol. 2004; 25: 47-52Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar, M. killer cell in the of immune 2005; PubMed Scopus Google Scholar we that CCR4 may DC contacts with conventional NK cells. DCs and macrophages are of and known to NK cell maturation, and cross talk to reduced contacts in CS-exposed CCR4−/− mice the of NK cell have now demonstrated CCR4 of NK cell activation in and CS exposure that during CCR4 promotes contacts of NK cells with or macrophages. conditions, in no effector response to of In expression of and for rapid effector cell NK cells to inflammatory such as CXCL10, reportedly produced by J.C. S. D. epithelial cells in and in infection.Am J 2005; PubMed Scopus Google Scholar and cells on with In CS exposure elicits a rapid innate activation of NK cells and of NKG2D in the which are significantly on CCR4 demonstrate a for CCR4 in mediating in contacts between NK and cells, CCR4 in effector cross talk in the lung. studies are to the of CCR4 on the of long-term CS with and confocal of and in the mouse lung. of using flow CD11c+ cells were cells based on and The cells were and were for and populations were of and in mouse cells were in parenchymal and but expression was to cells with of and parenchymal cells with cells with and and DCs with dendritic the of the expression was polarized to the of the cells. with of in of CS-exposed and mice. were and to flow to and are to mice with of expression with lung CD11c+ cells in and of mouse cells with and with knockout mice of NK cell of and CCR4−/− mice were to flow to and lymphoid NK cell cells for and were and controls were and in flow are CCR4−/− of conventional NK cell