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.
    Frontiers in Immunology 05/2014; 5:217. DOI:10.3389/fimmu.2014.00217
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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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    ABSTRACT: Chronic mucocutaneous candidiasis disease (CMCD) may be caused by autosomal dominant (AD) IL-17F deficiency or autosomal recessive (AR) IL-17RA deficiency. Here, using whole-exome sequencing, we identified heterozygous germline mutations in STAT1 in 47 patients from 20 kindreds with AD CMCD. Previously described heterozygous STAT1 mutant alleles are loss-of-function and cause AD predisposition to mycobacterial disease caused by impaired STAT1-dependent cellular responses to IFN-γ. Other loss-of-function STAT1 alleles cause AR predisposition to intracellular bacterial and viral diseases, caused by impaired STAT1-dependent responses to IFN-α/β, IFN-γ, IFN-λ, and IL-27. In contrast, the 12 AD CMCD-inducing STAT1 mutant alleles described here are gain-of-function and increase STAT1-dependent cellular responses to these cytokines, and to cytokines that predominantly activate STAT3, such as IL-6 and IL-21. All of these mutations affect the coiled-coil domain and impair the nuclear dephosphorylation of activated STAT1, accounting for their gain-of-function and dominance. Stronger cellular responses to the STAT1-dependent IL-17 inhibitors IFN-α/β, IFN-γ, and IL-27, and stronger STAT1 activation in response to the STAT3-dependent IL-17 inducers IL-6 and IL-21, hinder the development of T cells producing IL-17A, IL-17F, and IL-22. Gain-of-function STAT1 alleles therefore cause AD CMCD by impairing IL-17 immunity.
    Journal of Experimental Medicine 08/2011; 208(8):1635-48. DOI:10.1084/jem.20110958 · 12.52 Impact Factor
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    ABSTRACT: Interleukin (IL)-27, a member of IL-12/IL-23 heterodimeric family of cytokines, has pleiotropic properties that can enhance or limit immune responses. IL-27 acts on various cell types, including T cells, B cells, macrophages, dendritic cells, natural killer (NK) cells and non-hematopoietic cells. Intensive studies have been conducted especially on T cells, revealing that various subsets of T cells respond uniquely to IL-27. IL-27 induces expansion of Th1 cells by activating signal transducer and activator of transcription (STAT) 1-mediated T-bet signaling pathway. On the other hand, IL-27 suppresses immune responses through inhibition of the development of T helper (Th) 17 cells and induction of IL-10 production in a STAT1- and STAT3-dependent manner. IL-27 is a potentially promising cytokine for therapeutic approaches on various human diseases. Here, we provide an overview of the biology of IL-27 related to T cell subsets, its structure, and production mechanism.
    International Journal of Molecular Sciences 02/2015; 16(2):2851-2863. DOI:10.3390/ijms16022851 · 2.86 Impact Factor
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