T-bet represses TH17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt

Lazarevic, Vanja; Chen, Xi; Shim, Jae Hyuck; Hwang, Eun Sook; Jang, Eue Soon; Bolm, Alexandra N.; Oukka, Mohamed; Kuchroo, Vijay K.; Glimcher, Laurie H.

doi:10.1038/ni.1969

Cited by 334 publications

(339 citation statements)

References 46 publications

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“…Indeed, IL-2 produced by Th1 cells activates STAT5, which competes with STAT3 for binding at the IL-17A promoter (31). Moreover, the Th1 lineage-determining factor T-bet inhibits Th17 differentiation by preventing the transactivation of the RORγT gene (32). Thus, the higher T-cell production of IL-17A that we observed in males may, in part, be a consequence of lowered IFNγ production by these cells.…”

Section: Discussionmentioning

confidence: 56%

Peroxisome proliferator-activated receptor (PPAR)α and -γ regulate IFNγ and IL-17A production by human T cells in a sex-specific way

Zhang

Rego

Moshkova

et al. 2012

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

199

177

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Women develop certain autoimmune diseases more often than men. It has been hypothesized that this may relate to the development of more robust T-helper (Th)1 responses in women. To test whether women exhibit a Th1 bias, we isolated naïve cluster of differentiation (CD)4 + T cells from peripheral blood of healthy women and men and measured the proliferation and cytokine production by these cells in response to submaximal amounts of anti-CD3 and anti-CD28. We observed that CD4 + T cells from women produced higher levels of IFNγ as well as tended to proliferate more than male CD4 + T cells. Intriguingly, male CD4 + T cells instead had a predilection toward IL-17A production. This sex dichotomy in Th cytokine production was found to be even more striking in the Swiss/Jackson Laboratory (SJL) mouse. Studies in mice and humans indicated that the sexual dimorphism in Th1 and Th17 cytokine production was dependent on the androgen status and the T-cell expression of peroxisome proliferator activated receptor (PPAR)α and PPARγ. Androgens increased PPARα and decreased PPARγ expression by human CD4 + T cells. PPARα siRNA-mediated knockdown had the effect of increasing IFNγ by male CD4 + T cells, while transfection of CD4 + T cells with PPARγ siRNAs increased IL-17A production uniquely by female T cells. Together, our observations indicate that human T cells exhibit a sex difference in the production of IFNγ and IL-17A that may be driven by expressions of PPARα and PPARγ. autoimmunity | cytokines | experimental autoimmune encephalomyelitis | gender | nuclear receptor

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Section: Discussionmentioning

confidence: 56%

Peroxisome proliferator-activated receptor (PPAR)α and -γ regulate IFNγ and IL-17A production by human T cells in a sex-specific way

Zhang

Rego

Moshkova

et al. 2012

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

199

177

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“…Therefore, although expression of RORC2 can drive IL-17 production, it is not sufficient confer the epigenetic modifications at the IFNG and TBX21 loci, which would be required for conversion to the Th17 cell lineage. In contrast, ectopic expression of T-bet is sufficient to repress RORgt expression and convert in vitro-differentiated mouse Th17 cells into Th1 cells (49). Together, these data suggest there may be a hierarchy of transcription factor regulation in which T-BET can suppress RORC2 transcription but RORC2 cannot suppress TBX21.…”

Section: Discussionmentioning

confidence: 66%

Human Th1 and Th17 Cells Exhibit Epigenetic Stability at Signature Cytokine and Transcription Factor Loci

Cohen

Crome

MacDonald

et al. 2011

The Journal of Immunology

103

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The linear model of Th cell lineage commitment is being revised due to reports that mature Th cells can trans-differentiate into alternate lineages. This ability of Th cells to reprogram is thought to be regulated by epigenetic mechanisms that control expression of transcription factors characteristic of opposing lineages. It is unclear, however, to what extent this new model of Th cell plasticity holds true in human Th cell subsets that develop under physiological conditions in vivo. We isolated in vivo-differentiated human Th1 and Th17 cells, as well as intermediate Th1/17 cells, and identified distinct epigenetic signatures at cytokine (IFNG and IL17A) and transcription factor (TBX21, RORC, and RORA) loci. We also examined the phenotypic and epigenetic stability of human Th17 cells exposed to Th1-polarizing conditions and found that although they could upregulate TBX21 and IFN-γ, this occurred without loss of IL-17 or RORC expression, and resulted in cells with a Th1/17 phenotype. Similarly, Th1 cells could upregulate IL-17 upon enforced expression of RORC2, but did not lose expression of IFN-γ or TBX21. Despite alterations in expression of these signature genes, epigenetic modifications were remarkably stable aside from the acquisition of active histone methylation marks at cytokine gene promoters. The limited capacity of human Th17 and Th1 cells to undergo complete lineage conversion suggests that the bipotent Th1/17 cells may arise from Th1 and/or Th17 cells. These data also question the broad applicability of the new model of Th cell lineage plasticity to in vivo-polarized human Th cell subsets.

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“…IL-17 has been shown to directly or indirectly induce destruction of bone and cartilage (Sato et al 2006), and other IL-17 family members, including IL-17F, have been implicated in inflammatory diseases, autoimmune diseases and cancer (Kolls et al 2004). The key transcription factor behind the expression of these cytokines and the Th17 subset is the orphan nuclear receptor RORγt (Ivanov et al 2006;Lazarevic et al 2011). Th17 cells are induced by IL-6 and TGF-β, and are maintained by IL-23 (Aggarwal et al 2003;Harrington et al 2005;Park et al 2005;Iwakura et al 2006;McKenzie et al 2006).…”

Section: Discussionmentioning

confidence: 99%

Effects of exposure to extremely low-frequency electromagnetic fields on the differentiation of Th17 T cells and regulatory T cells

Lee

Hyung²,

Yoo³

et al. 2016

gpb

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Abstract. The potential risks that electromagnetic fields (EMF) pose to human physiology have been debated for several decades, especially considering that EMF is almost omnipresent and some occupations involve regular exposure to particularly strong fields. In the present study, the effects of 60 Hz 0.3 mT EMF on CD4 + T cells were evaluated. Production of T cell related cytokines, IFN-γ and IL-2, was not altered in CD4 + T cells that were exposed to EMF, and cell proliferation was also unaffected. The expression of genes present in a subset of Th17 cells was upregulated following EMF exposure, and the production of effector cytokines of the IL-17A subset also increased. To determine signaling pathways that underlie these effects, phosphorylation of STAT3 and SMAD3, downstream molecules of cytokines critical for Th17 induction, was analyzed. Increased SMAD3 phosphorylation level in cells exposed to EMF, suggesting that SMAD3 may be at least in part causing the increased Th17 cell production. Differentiation of Treg, another CD4 + T cell subset induced by SMAD3 signaling, was also elevated following EMF exposure. These results suggest that 60 Hz 0.3 mT EMF exposure amplifies TGF-β signaling and increases the generation of specific T cell subsets.

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T-bet represses TH17 differentiation by preventing Runx1-mediated activation of the gene encoding RORγt

Cited by 334 publications

References 46 publications

Peroxisome proliferator-activated receptor (PPAR)α and -γ regulate IFNγ and IL-17A production by human T cells in a sex-specific way

Peroxisome proliferator-activated receptor (PPAR)α and -γ regulate IFNγ and IL-17A production by human T cells in a sex-specific way

Human Th1 and Th17 Cells Exhibit Epigenetic Stability at Signature Cytokine and Transcription Factor Loci

Effects of exposure to extremely low-frequency electromagnetic fields on the differentiation of Th17 T cells and regulatory T cells

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