IFNγ Signaling Endows DCs with the Capacity to Control Type I Inflammation during Parasitic Infection through Promoting T-bet+ Regulatory T Cells

Lee, Hyang-Mi; Fleige, Anne; Forman, Ruth; Cho, Sunglim; Khan, Aly A.; Lin, Ling-Li; Nguyen, Duc T.; Hall, Aisling O’Hara; Yin, Zhinan; Hunter, Christopher A.; Müller, Werner; Lu, Li-Fan

doi:10.1371/journal.ppat.1004635

Cited by 25 publications

(27 citation statements)

References 38 publications

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“…3 This observation highlights that, indeed, 35,36 we evaluated the Treg cell chemokine receptor profile. In line with several previous reports, including our own report, 17,[21][22][23][24][25][26][27][28]37 we found robust expression of the Th1-characteristic receptor CXCR3 on splenic and renal Treg cells. Intriguingly, however, CXCR3 expression was completely abrogated on Treg cells from Foxp3 Cre xT-bet fl/fl mice, indicating absolute dependency on T-bet activation.…”

Section: Discussionsupporting

confidence: 93%

“…Close colocalization in inflamed tissues might be achieved by shared expression of the Th1-characteristic chemokine receptor CXCR3, 19 which has also been shown by us to mediate renal trafficking of Th1 cells in cGN. 20 In line with this hypothesis, various studies have shown coincidental upregulation of CXCR3 and T-bet on Treg cells during Th1-type inflammation caused by infection, cancer, contact hypersensitivity, autoimmunity, or organ transplantation in mice [21][22][23][24] and humans. [25][26][27][28] Although all of these studies point toward a role of T-bet in Treg cells for enhancing their immunosuppressive capacity specifically against Th1 responses, a recent study has reported opposing effects.…”

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confidence: 84%

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T-Bet Enhances Regulatory T Cell Fitness and Directs Control of Th1 Responses in Crescentic GN

Nosko¹,

Kluger²,

Diefenhardt³

et al. 2016

JASN

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Th1 cells are central pathogenic mediators of crescentic GN (cGN). Mechanisms responsible for Th1 cell downregulation, however, remain widely unknown. Recently, it was proposed that activation of the Th1-characteristic transcription factor T-bet optimizes Foxp3 regulatory T (Treg) cells to counteract Th1-type inflammation. Because very little is known about the role of T-bet Treg1 cells in inflammatory diseases, we studied the function of these cells in the nephrotoxic nephritis (NTN) model of cGN. The percentage of Treg1 cells progressively increased in kidneys of nephritic wild-type mice during the course of NTN, indicating their functional importance. Notably, naïve Foxp3xT-bet mice, lacking Treg1 cells, showed spontaneous skewing toward Th1 immunity. Furthermore, absence of Treg1 cells resulted in aggravated NTN with selectively dysregulated renal and systemic Th1 responses. Detailed analyses of Treg cells from Foxp3xT-bet mice revealed unaltered cytokine production and suppressive capacity. However, in competitive cotransfer experiments, wild-type Treg cells outcompeted T-bet-deficient Treg cells in terms of population expansion and expression levels of Foxp3, indicating that T-bet expression is crucial for general Treg fitness. Additionally, T-bet-deficient Treg cells lacked expression of the Th1-characteristic trafficking receptor CXCR3, which correlated with significant impairment of renal Treg infiltration. In summary, our data indicate a new subtype of Treg cells in cGN. These Treg1 cells are characterized by activation of the transcription factor T-bet, which enhances the overall fitness of these cells and optimizes their capacity to downregulate Th1 responses by inducing chemokine receptor CXCR3 expression.

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Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 84%

T-Bet Enhances Regulatory T Cell Fitness and Directs Control of Th1 Responses in Crescentic GN

Nosko¹,

Kluger²,

Diefenhardt³

et al. 2016

JASN

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“…All mice were on a C57Bl/6 background. Female LDLR -/-, IFNgR2 fl/fl (IFNgR2 wt ) and LysMCre-IFNgR2 fl/fl (IFNgR2 del ) [16] littermates were house bred at the breeding facility of the Academic Medical Center (Amsterdam, The Netherlands) according to guidelines of the Animal Research Ethics Committee of the University of Amsterdam. IFNgR2 À/À (IFNgR2 KO ) mice were generated at the Helmholtz Institute for Infection Research, Braunschweig, Germany.…”

Section: Micementioning

confidence: 99%

Myeloid interferon-γ receptor deficiency does not affect atherosclerosis in LDLR-/- mice

et al. 2016

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“…In this study, we have investigated the cell population(s) and compartments that IFN-γR signals within to mediate ECM development during P. berghei ANKA infection. Utilizing novel cell- and compartment-specific IFN-γR2-deficient mice ( 31 ), we demonstrate that IFN-γ causes ECM by signaling within both the hematopoietic and nonhematopoietic compartments. Within the brain, IFN-γR signaling within the two compartments was additive, which led to severe neuroinflammation.…”

Section: Introductionmentioning

confidence: 99%

Gamma Interferon Mediates Experimental Cerebral Malaria by Signaling within Both the Hematopoietic and Nonhematopoietic Compartments

et al. 2017

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Experimental cerebral malaria (ECM) is a gamma interferon (IFN-γ)-dependent syndrome. However, whether IFN-γ promotes ECM through direct and synergistic targeting of multiple cell populations or by acting primarily on a specific responsive cell type is currently unknown. Here, using a panel of cell- and compartment-specific IFN-γ receptor 2 (IFN-γR2)-deficient mice, we show that IFN-γ causes ECM by signaling within both the hematopoietic and nonhematopoietic compartments. Mechanistically, hematopoietic and nonhematopoietic compartment-specific IFN-γR signaling exerts additive effects in orchestrating intracerebral inflammation, leading to the development of ECM. Surprisingly, mice with specific deletion of IFN-γR2 expression on myeloid cells, T cells, or neurons were completely susceptible to terminal ECM. Utilizing a reductionist in vitro system, we show that synergistic IFN-γ and tumor necrosis factor (TNF) stimulation promotes strong activation of brain blood vessel endothelial cells. Combined, our data show that within the hematopoietic compartment, IFN-γ causes ECM by acting redundantly or by targeting non-T cell or non-myeloid cell populations. Within the nonhematopoietic compartment, brain endothelial cells, but not neurons, may be the major target of IFN-γ leading to ECM development. Collectively, our data provide information on how IFN-γ mediates the development of cerebral pathology during malaria infection.

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IFNγ Signaling Endows DCs with the Capacity to Control Type I Inflammation during Parasitic Infection through Promoting T-bet+ Regulatory T Cells

Cited by 25 publications

References 38 publications

T-Bet Enhances Regulatory T Cell Fitness and Directs Control of Th1 Responses in Crescentic GN

T-Bet Enhances Regulatory T Cell Fitness and Directs Control of Th1 Responses in Crescentic GN

Myeloid interferon-γ receptor deficiency does not affect atherosclerosis in LDLR-/- mice

Gamma Interferon Mediates Experimental Cerebral Malaria by Signaling within Both the Hematopoietic and Nonhematopoietic Compartments

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