Natural Killer T (NKT) Cells Attenuate Bleomycin-Induced Pulmonary Fibrosis by Producing Interferon-γ

Kim, Ji Hyung; Kim, Hye Young; Kim, Sanghee; Chung, Jin Haeng; Park, Weon Seo; Chung, Doo Hyun

doi:10.1016/s0002-9440(10)61211-4

Cited by 79 publications

(67 citation statements)

References 46 publications

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“…34 In line with the current studies, there is growing literature that certain subsets of T cells are beneficial because mice with severe combined immunodeficiency developed more severe fibrosis in response to asbestos, which was reduced on reconstitution with T cells. 11 Furthermore, use of mice deficient in natural killer T cells 35 or ␥␦ T cells 36 has shown worsened fibrosis, suggesting that specific subsets of T cells are responsible for regulating fibrosis.…”

Section: Discussionmentioning

confidence: 99%

γδ T Cells Attenuate Bleomycin-Induced Fibrosis through the Production of CXCL10

Pociask

Chen

Choi

et al. 2011

The American Journal of Pathology

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␥␦ T cells are a subset of T cells associated with epithelial mucosal tissues and play a prominent role in both promoting and dampening inflammatory responses to pathogens; in addition, they strongly mediate epithelial repair. By using a bleomycin model of pulmonary fibrosis, we found that ␥␦ T-cell populations dramatically increased after bleomycin administration. To determine the importance of these cells, we exposed mice lacking the ␦ chain of the ␥␦ T-cell receptor (␥␦ knockout [KO]) to bleomycin. Pulmonary fibrosis was more severe in ␥␦ KO mice, as measured by collagen deposition (hydroxyproline) and histopathological features. Furthermore, there was no evidence of resolution of the fibrotic response up to 45 days after bleomycin therapy. In contrast to control mice, ␥␦ KO mice had decreased concentrations of IL-6, granulocyte colony stimulating factor, chemokine CXC ligand (CXCL) 1, and interferon inducible protein 10/CXCL10. In vitro culture of ␥␦ T cells purified from lungs 17 days after bleomycin exposure (a time of peak influx of these cells) demonstrated that ␥␦ T cells produced substantial quantities of all four of these cytokines, suggesting that ␥␦ T cells are a predominant source of these proteins. To demonstrate that ␥␦ T cells are effector cells in the fibrotic response, we performed adoptive transfer experiments with ␥␦ T cells sorted from bleomycin-treated lungs; these cells were sufficient to resolve fibrosis in ␥␦ KO mice and restore CXCL10 levels comparable to wild-type mice. Furthermore, overexpression of CXCL10 in the lung decreased the severity of fibrosis seen in the ␥␦ KO mice. Finally, adoptive transfer of ␥␦ T cells from CXCL10 ؊/؊ mice failed to reverse the severe fibrosis in ␥␦ KO mice. These results indicate that ␥␦ T cells promote the resolution of fibrosis through the production of

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Section: Discussionmentioning

confidence: 99%

γδ T Cells Attenuate Bleomycin-Induced Fibrosis through the Production of CXCL10

Pociask

Chen

Choi

et al. 2011

The American Journal of Pathology

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“…1,4 Therefore, NKT cells regulate various immune responses related to autoimmune diseases, hypersensitivity pneumonia, pulmonary fibrosis, oral tolerance, transplantation rejection, and graftversus-host disease. 1,[4][5][6][7][8][9][10] In addition, they enhance the immune response to tumors, microorganisms, and inflammation. 4,11,12 The results of a recent phase I clinical trial using Va24 NKT cells activated by a-galactosyl ceramide (a-GalCer) in patients with advanced and recurrent nonsmall-cell cancer 13 suggested that activating reagents for NKT cells may be good candidates for regulating immune disease.…”

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confidence: 99%

FTY720, a sphingosine 1-phosphate receptor modulator, inhibits CD1d-restricted NKT cells by suppressing cytokine production but not migration

Hwang

Kim

et al. 2010

Laboratory Investigation

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FTY720, a sphingosine 1-phosphate (S1P) receptor modulator, suppresses immune responses by inhibiting T-cell migration into target tissues; however, it does not alter T-cell functions. In this study, we investigated the biological effects of FTY720 on NKT cells. Unlike T cells, FTY720 suppressed the production of IL-4, IFN-g, IL-10, and IL-13 by NKT cells through the S1P1 receptor (S1P 1 ). Moreover, FTY720 also inhibited the expression of T-bet and GATA-3 of NKT cells in the presence of TCR engagement. However, it did not inhibit NKT cell migration in vitro or in vivo. In a K/BxN serum transfer arthritis model, FTY720 suppressed arthritis in B6, but not in CD1d À/À mice. Moreover, the adoptive transfer of control NKT cells restored arthritis in CD1d À/À mice, whereas FTY720-pretreated NKT cells did not. The number of NKT cells in the joints of B6 mice given FTY720 was similar to that in the joints of untreated B6 mice, whereas the production of IL-4 and IFN-g was reduced in the FTY720-treated B6 mice. Taken together, these data show that FTY720 suppresses cytokine production in NKT cells through S1P 1 , but not NKT cell migration. Thus, FTY720 may be useful in the treatment of NKT cell-promoted immune diseases.

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“…NKT cells play critical roles in various immune responses in vivo, e.g., in the maintenance of self-tolerance, in autoimmune diseases (2)(3)(4), in tumor rejection (5), in pulmonary fibrosis (6), and in response to various infectious agents (7)(8)(9). Upon activation, NKT cells rapidly produce large amounts of IL-4 and IFN-␥ (10), which play critical roles in the regulation of innate and adaptive immune responses (1).…”

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Engagement of Glucocorticoid-Induced TNF Receptor Costimulates NKT Cell Activation In Vitro and In Vivo

Kim

et al. 2006

The Journal of Immunology

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Glucocorticoid-induced TNF receptor (GITR) is known to provide costimulatory signals to CD4+CD25− and CD4+CD25+ T cells during immune responses in vivo. However, the functional roles of GITR expressed on NKT cells have not been well characterized. In this study, we have explored the functions of GITR as a costimulatory factor on NKT cells. GITR was found to be constitutively expressed on NKT cells and its expression was enhanced by TCR signals. GITR engagement using DTA-1, an agonistic mAb against GITR, in the presence of TCR signals, augmented IL-2 production, the expression of activation markers, cell cycle progression, and the nuclear translocations of NF-κB p50 and p65. Furthermore, GITR engagement enhanced the production of IL-4, IL-10, IL-13, and IFN-γ by NKT cells and the expression level of phosphorylated p65 in NKT cells in the presence of TCR engagement, indicating that GITR provides costimulatory signals to NKT cells. The costimulatory effects of GITR on NKT cells were comparable to those of CD28 in terms of cytokine production. Moreover, the coinjection of DTA-1 and α-galactosylceramide into B6 mice induced more IL-4 and IFN-γ production than the coinjection of control mAbs and α-galactosylceramide. In addition, the adoptive transfer of DTA-1-pretreated NKT cells into CD1d−/− mice attenuated hypersensitivity pneumonitis more than control IgG pretreated NKT cells in these mice. These findings demonstrate that GITR engagement on NKT cells modulates immune responses in hypersensitivity pneumonitis in vivo. Taken together, our findings suggest that GITR engagement costimulates NKT cells and contributes to the regulation of immune-associated disease processes in vivo.

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Natural Killer T (NKT) Cells Attenuate Bleomycin-Induced Pulmonary Fibrosis by Producing Interferon-γ

Cited by 79 publications

References 46 publications

γδ T Cells Attenuate Bleomycin-Induced Fibrosis through the Production of CXCL10

γδ T Cells Attenuate Bleomycin-Induced Fibrosis through the Production of CXCL10

FTY720, a sphingosine 1-phosphate receptor modulator, inhibits CD1d-restricted NKT cells by suppressing cytokine production but not migration

Engagement of Glucocorticoid-Induced TNF Receptor Costimulates NKT Cell Activation In Vitro and In Vivo

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