Activating Immunity in the Liver. I. Liver Dendritic Cells (but Not Hepatocytes) Are Potent Activators of IFN-γ Release by Liver NKT Cells

Trobonjača, Zlatko; Leithäuser, Frank; Möller, Peter; Schirmbeck, Reinhold; Reimann, Joerg

doi:10.4049/jimmunol.167.3.1413

Cited by 105 publications

(93 citation statements)

References 69 publications

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“…␣-GalCer needs to be presented via CD1d on APCs to activate NKT cells (19,25,61). Because CXCL16 is expressed as a transmembrane molecule on activated DCs and macrophages (44,53), it is possible that CXCR6/CXCL16 interactions mediate cell-cell adhesion and/or provide costimulatory signals that up-regulate NKT cell function.…”

Section: Discussionmentioning

confidence: 99%

Critical Role for the Chemokine Receptor CXCR6 in Homeostasis and Activation of CD1d-Restricted NKT Cells

Germanov¹,

Veinotte²,

Cullen³

et al. 2008

The Journal of Immunology

103

109

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NK T (NKT) cells play important roles in the regulation of diverse immune responses. However, little is known about the mechanisms that regulate homeostasis and activation of these cells. Thymic NKT cells up-regulated the chemokine receptor CXCR6 following positive selection and migrated toward CXCL16 in vitro. However, CXCR6 was not essential for thymic development or maturation. In contrast, liver and lung NKT cells were depleted in CXCR6+/− and CXCR6−/− mice. The reduction in liver and lung NKT cells coincided with an increase in bone marrow NKT cells, suggesting a redistribution of NKT cells in CXCR6−/− animals. In wild-type mice, CXCL16 neutralization reduced accumulation of mature NK1.1+, but not immature NK1.1− NKT cell recent thymic emigrants in the liver. Given that thymic NKT cells are preferentially exported as NK1.1− cells, this suggests an additional role for CXCR6/CXCL16 in maturation or survival of immature liver NKT cells. CXCL16 blockade did not deplete resident NK1.1+ NKT cells, indicating that CXCR6/CXCL16 are not required to retain mature NKT cells in the liver. Cytokine production by liver and spleen NKT cells was impaired in CXCR6−/− mice following in vivo stimulation with α-galactosylceramide, implicating a novel role for CXCR6 in NKT cell activation. Reduced IFN-γ production was not due to an intrinsic defect as production was normal following PMA and ionomycin stimulation. Preformed transcripts for IL-4, but not IFN-γ, were reduced in CXCR6−/− liver NKT cells. These data identify critical roles for CXCR6/CXCL16 in NKT cell activation and the regulation of NKT cell homeostasis.

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Section: Discussionmentioning

confidence: 99%

Critical Role for the Chemokine Receptor CXCR6 in Homeostasis and Activation of CD1d-Restricted NKT Cells

Germanov¹,

Veinotte²,

Cullen³

et al. 2008

The Journal of Immunology

103

109

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“…Similarly, ␣-C-GalCer is able to stimulate secondary production of IFN-␥ by NK cells even though it is a weak stimulus for primary cytokine production by NK T cells (12). The downstream IFN-␥ stimulated by ␣-GalCer or ␣-C-GalCer requires the concomitant production of IL-12 (12, 23), which a number of studies suggest comes from DCs (17)(18)(19)…”

Section: Dcs Act As Apcs For Splenic But Not Hepatic Nk T Cellsmentioning

confidence: 99%

“…Fujii et al (14) showed that DCs loaded with ␣-GalCer and adoptively transferred into na ve mice stimulated a better NK T cell response in vivo than that stimulated by injection of free compound. Other studies have demonstrated the ability of ␣-GalCer to induce maturation of both splenic and hepatic DCs in vivo (15,16), and others have shown the importance of DCs as sources of ␣-GalCer-induced IL-12 (17)(18)(19).…”

mentioning

confidence: 99%

Glycolipid presentation to natural killer T cells differs in an organ-dependent fashion

Schmieg

Yang

Franck

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

113

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“…Consistent with studies of hepatic DCs propagated from DC progenitors in vitro, it was shown that freshly isolated liver DCs were immature, with low MHC class II and costimulatory molecule (CD40, CD80, and CD86) expression. 9 The ability of freshly isolated liver DCs to stimulate T cells has not been well defined. …”

mentioning

confidence: 99%

GM-CSF expands dendritic cells and their progenitors in mouse liver

Pillarisetty

2003

Hepatology

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Dendritic cells (DCs) are rare but ubiquitous antigen-presenting cells situated in lymphoid and nonlymphoid organs throughout the body. The study of DCs located in the liver has been restricted by their relative scarcity and the difficulty of their isolation. Because granulocyte-macrophage colony-stimulating factor (GM-CSF) is a critical growth factor for DCs in vitro, we postulated that it would expand hepatic DCs in vivo. We found that adenoviralmediated GM-CSF overexpression in normal mice increased the number of liver DCs 400-fold to more than 100 million cells. GM-CSF-recruited DCs were CD11c ؉ DEC205 ؊ and had high expression of major histocompatibility complex (MHC) class II, CD54, and CD80 but low CD40 and CD86 staining. Further maturation occurred after overnight culture. In addition to CD11c ؉ DEC205 ؊ DCs, a population of CD11c ؊ DEC205 low/؊ cells resembling DC progenitors described previously in normal mice was expanded as serum GM-CSF levels increased. GM-CSF-recruited CD11c D endritic cells (DCs) are rare, heterogeneous leukocytes that are primarily responsible for the capture of antigens in the periphery and subsequent presentation to immune effector cells. 1-3 Although there is a large and rapidly expanding body of data regarding the phenotype and function of murine bone marrowderived DCs and splenic DCs, our understanding of hepatic DCs is rudimentary. [4][5][6] This is due to the scarcity of hepatic DCs and the difficulty of isolating them from normal mice. Most of our knowledge emanates from using granulocyte-macrophage colony-stimulating factor (GM-CSF) to propagate liver DCs in vitro from DC progenitors contained within hepatic nonparenchymal cells (NPCs). 7,8 This approach is analogous to the method commonly used to produce DCs from bone marrow cells. 4 Hepatic DC progenitors have low expression of major histocompatibility complex (MHC) class II and the DC-restricted markers DEC205, CD11c, and 33D1 and produce only low levels of allostimulation in a mixed leukocyte reaction. 7 However, they can differentiate (i.e., gain CD11c and MHC class II expression) into immature DCs in vitro in the presence of GM-CSF. After additional culture on type-1 collagen, the immature liver DCs then become mature with increased surface costimulatory molecule expression and T-cell stimulatory capacity. 7 More recently, the phenotype of freshly isolated CD11c ϩ liver DCs has been described. Consistent with studies of hepatic DCs propagated from DC progenitors in vitro, it was shown that freshly isolated liver DCs were immature, with low MHC class II and costimulatory molecule (CD40, CD80, and CD86) expression. 9 The ability of freshly isolated liver DCs to stimulate T cells has not been well defined.

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Activating Immunity in the Liver. I. Liver Dendritic Cells (but Not Hepatocytes) Are Potent Activators of IFN-γ Release by Liver NKT Cells

Cited by 105 publications

References 69 publications

Critical Role for the Chemokine Receptor CXCR6 in Homeostasis and Activation of CD1d-Restricted NKT Cells

Critical Role for the Chemokine Receptor CXCR6 in Homeostasis and Activation of CD1d-Restricted NKT Cells

Glycolipid presentation to natural killer T cells differs in an organ-dependent fashion

GM-CSF expands dendritic cells and their progenitors in mouse liver

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