STAT1-Activating Cytokines Limit Th17 Responses through Both T-bet-Dependent and -Independent Mechanisms

Department of Pathology, University of California San Francisco, San Francisco, CA 94143, USA.
The Journal of Immunology (Impact Factor: 4.92). 10/2010; 185(11):6461-71. DOI: 10.4049/jimmunol.1001343
Source: PubMed


Given the association with autoimmune disease, there is great interest in defining cellular factors that limit overactive or misdirected Th17-type inflammation. Using in vivo and in vitro models, we investigated the molecular mechanisms for cytokine-mediated inhibition of Th17 responses, focusing on the role of STAT1 and T-bet in this process. These studies demonstrate that, during systemic inflammation, STAT1- and T-bet-deficient T cells each exhibit a hyper-Th17 phenotype relative to wild-type controls. However, IL-17 production was greater in the absence of T-bet, and when both STAT1 and T-bet were deleted, there was no further increase, with the double-deficient cells instead behaving more like STAT1-deficient counterparts. Similar trends were observed during in vitro priming, with production of Th17-type cytokines greater in T-bet(-/-) T cells than in either STAT1(-/-) or STAT1(-/-) T-bet(-/-) counterparts. The ability of IFN-γ and IL-27 to suppress Th17 responses was reduced in T-bet-deficient cells, and most importantly, ectopic T-bet could suppress signature Th17 gene products, including IL-17A, IL-17F, IL-22, and retinoic acid-related orphan receptor γT, even in STAT1-deficient T cells. Taken together, these studies formally establish that, downstream of IFN-γ, IL-27, and likely all STAT1-activating cytokines, there are both STAT1 and T-bet-dependent pathways capable of suppressing Th17 responses.

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Available from: Alejandro V Villarino, Sep 26, 2014
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    • "T-bet was originally defined as the master regulatory transcription factor involved in promoting TH1 CD4+ T-cell development while specifically inhibiting TH2 and TH17 lineage-defining programs in murine models (4–7). T-bet is known to modulate a number of genes involved in T-cell mobilization (CXCR3), cell signaling (IL12Rβ1), and cytolytic signaling molecules (IFNγ) (8). "
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    ABSTRACT: The T-box transcription factors T-bet and Eomesodermin (Eomes) have been well defined as key drivers of immune cell development and cytolytic function. While the majority of studies have defined the roles of these factors in the context of murine T-cells, recent results have revealed that T-bet, and possibly Eomes, are expressed in other immune cell subsets. To date, the expression patterns of these factors in subsets of human peripheral blood mononuclear cells beyond T-cells remain relatively uncharacterized. In this study, we used multiparametric flow cytometry to characterize T-bet and Eomes expression in major human blood cell subsets, including total CD4(+) and CD8(+) T-cells, γδ T-cells, invariant NKT cells, natural killer cells, B-cells, and dendritic cells. Our studies identified novel cell subsets that express T-bet and Eomes and raise implications for their possible functions in the context of other human immune cell subsets besides their well-known roles in T-cells.
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    • "The mutant STAT1 alleles described herein enhance cellular responses to cytokines such as IFN-/, IFN-, and IL-27, which potently inhibit the development of IL-17– producing T cells via STAT1 (Batten et al., 2006; Yoshimura et al., 2006; Stumhofer et al., 2006; Amadi-Obi et al., 2007; Feng et al., 2008; Kimura et al., 2008; Tanaka et al., 2008; Chen et al., 2009; Ramgolam et al., 2009; Crabé et al., 2009; Diveu et al., 2009; El-behi et al., 2009; Guzzo et al., 2010; Villarino et al., 2010; Liu and Rohowsky-Kochan, 2011). These mutant alleles also increase cellular responses to IL-6 and IL-21, which normally induce IL-17–producing T cells via STAT3 rather than STAT1 (Hirahara et al., 2010). "
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