Transcription Factor Smad-Independent T Helper 17 Cell Induction by Transforming-Growth Factor-β Is Mediated by Suppression of Eomesodermin

Ichiyama, Kenji; Sekiya, Takashi; Inoue, N.; Tamiya, Taiga; Kashiwagi, Ikko; Kimura, Akihiro; Morita, Rimpei; Muto, Go; Shichita, Takashi; Takahashi, Reiko; Yoshimura, Akihiko

doi:10.1016/j.immuni.2011.02.021

Cited by 123 publications

(116 citation statements)

References 66 publications

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“…Accordingly, we did not observe Eomes expression in IL-17-producing cells in vivo. The described Eomes-mediated Th17 repression was not complete, suggesting perhaps that there may be other pathways of Rorc and Il17 induction that are not inhibited by Eomes (26). In agreement with a minor role of Eomes for the inhibition of Th17 responses, we did not observe a significant increase in the frequency or total numbers of CD4 + Th17 cells in Eomes-KO mice either during the inflammatory response in colitis or during aging.…”

Section: Discussionsupporting

confidence: 75%

“…Previous reports indicate that Eomes RNA and protein are induced upon activation in vitro (8,26). Indeed, after 3 d of in vitro stimulation with anti-CD3 and IL-2, we found that a substantial fraction of cultured CD4 + CD45RB high T cells expressed Eomes (Fig.…”

Section: Eomes + Cd4 + T Cells Accumulate With Agesupporting

confidence: 58%

“…Reciprocally, the TGF-b-JNK-c-Jun signaling pathway was shown to repress Eomes during Th17 polarization (26). Accordingly, we did not observe Eomes expression in IL-17-producing cells in vivo.…”

Section: Discussionmentioning

confidence: 48%

“…Eomes has also been reported to repress the Th17 fate during CD4 + and CD8 + T cell polarization, although for the latter in a redundant way with T-bet (9,21,26). Reciprocally, the TGF-b-JNK-c-Jun signaling pathway was shown to repress Eomes during Th17 polarization (26).…”

Section: Discussionmentioning

confidence: 98%

“…T-bet and Eomes have been described to interact directly with GATA3 in a subset of Th2 memory cells, sequestering it away from the Il5 promoter and blocking IL-5 production (10,25). Eomes overexpression can also suppress Th17 differentiation by directly blocking transcription at both Rorc and Il17a loci (26). The role of Eomes in the development of CD4 + Foxp3 + Treg has not been determined to date.…”

Section: T He Cd4 + T Cells Coordinate Different Types Of Immunementioning

confidence: 99%

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Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

Lupar¹,

Brack

Garnier

et al. 2015

The Journal of Immunology

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CD4+ T cells polarize into effector Th subsets characterized by signature transcription factors and cytokines. Although T-bet drives Th1 responses and represses the alternative Th2, Th17, and Foxp3+ regulatory T cell fates, the role of the T-bet–related transcription factor eomesodermin (Eomes) in CD4+ T cells is less well understood. In this study, we analyze the expression and effects of Eomes in mouse CD4+ T lymphocytes. We find that Eomes is readily expressed in activated CD4+ Th1 T cells in vivo. Eomes+ CD4+ T cells accumulated in old mice, under lymphopenic conditions in a T cell transfer model of colitis, and upon oral Ag administration. However, despite its expression, genetic deletion of Eomes in CD4+ T cells did not impact on IFN-γ production nor increase Th2 or Th17 responses. In contrast, Eomes deficiency favored the accumulation of Foxp3+ cells in old mice, after in vivo differentiation of Eomes-deficient naive CD4+ T cells, and in response to oral Ag in a cell-intrinsic way. Enforced Eomes expression during in vitro regulatory T cell induction also reduced Foxp3 transcription. Likewise, bystander Eomes-deficient CD4+ T cells were more efficient at protecting from experimental autoimmune encephalitis compared with wild-type CD4+ T cells. This enhanced capacity of Eomes-deficient CD4+ T cells to inhibit EAE in trans was associated with an enhanced frequency of Foxp3+ cells. Our data identify a novel role for Eomes in CD4+ T cells and indicate that Eomes expression may act by limiting Foxp3 induction, which may contribute to the association of EOMES to susceptibility to multiple sclerosis.

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Section: Discussionsupporting

confidence: 75%

Section: Eomes + Cd4 + T Cells Accumulate With Agesupporting

confidence: 58%

Section: Discussionmentioning

confidence: 48%

Section: Discussionmentioning

confidence: 98%

Section: T He Cd4 + T Cells Coordinate Different Types Of Immunementioning

confidence: 99%

See 3 more Smart Citations

Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

Lupar¹,

Brack

Garnier

et al. 2015

The Journal of Immunology

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TGF‐β in the Immune Response

Nakatsukasa

Chia

et al. 2015

Encyclopedia of Life Sciences

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Transforming growth factor‐β (TGF‐β) is a highly evolutionally conserved cytokine that is critical for embryogenesis, cancer and matrix formation and immune responses. Three distinct isoforms, TGF‐β1, 2 and 3, are found in mammals. TGF‐β is secreted by immune and nonhematopoietic cells and acts on virtually all cell types through ubiquitously expressed receptors, which transduce the TGF‐β signal through canonical Smad‐dependent pathway and noncanonical Smad‐independent pathways. In particular, TGF‐β plays a crucial role in immune tolerance and maintains immune homeostasis by inhibiting proliferation, differentiation, activation and effector function of immune cells. On the other side of the coin, TGF‐β can display proinflammatory properties, depending on the context. The more complete understanding of the various functions of TGF‐β in the immune system, especially in tolerance, will enable us to design more specific and effective therapies for immune disorders. Key Concepts TGF‐β is a multifunctional cytokine that mainly suppresses immune responses to maintain immune homeostasis. TGF‐β signalling is transduced via not only its unique protein, Smad, but also via Smad‐independent pathways. T cells are the major targets of TGF‐β in immune system and its activation/proliferation, apoptosis and differentiation are regulated by TGF‐β. TGF‐β is a key mediator for the regulation of autoimmune diseases.

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The development of IL‐17/IFN‐γ‐double producing CTLs from Tc17 cells is driven by epigenetic suppression of Socs3 gene promoter

et al. 2012

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The plasticity of T lymphocytes induced by epigenetic modifications of gene promoters may play a pivotal role in controlling their effector functions, which are sometimes causally associated with immune disorders. IL -17-producing T cells, which induce type 17 immune responses, are newly identified pathogenic effector cells. The type 1 signature cytokine IFN-γ strongly inhibits their differentiation, indicating a mutually exclusive relationship between type 17-and type 1-immune responses. However, many reports indicate the presence of a unique IL-17/IFN-γ-double producing T-cell subset in various inflammatory settings, although the mechanisms responsible for their development and their precise functions remain unclear. Here, we demonstrate that IL-12 permits the conversion of mouse IL-17-producing CD8 + T (Tc17) cells to IL-17/IFN-γ-double producing CD8 + T (Tc17/IFN-γ) cells, and that this conversion is due to repressive epigenetic modifications of Socs3 gene promoters. Moreover, we show that SOCS3 strongly regulates the capability of Tc17 cells to produce IL-17, in addition to regulating the expression of the type 17-master regulator RORγt. These findings elucidate the mechanisms underlying the conversion of Tc17 cells into Tc17/IFN-γ cells. As these cells are known to have potent antitumor activities, manipulation of these conversion mechanisms for therapeutic tumor immunity may be possible. [3][4][5][6]. In particular, studies on Th17 cells enabled us to explain the precise mechanisms involved in several immune diseases, which could not be simply explained by disruption of the Th1/Th2 balance [7]. IL-17-producing CD8 + T (Tc17) cells are known to be * These authors contributed equally to this work. Keywords: Epigeneticswww.eji-journal.eu 2330 Takayuki Satoh et al. Eur. J. Immunol. 2012. 42: 2329-2342 induced under similar circumstances to Th17 cells, where IL-6 and TGF-β are crucial factors for induction and maintenance of the expression of retinoic acid-related orphan receptor γt (RORγt), the master regulator for type 17 immunity [8]. Furthermore, the presence of IFN-γ and IL-4 in the early stages negatively regulates the development of type 17 immune responses [5,6]. These reports clearly show that commitment toward a type 1, type 2, or type 17 immunity is an irreversible step, which inhibits commitment to another functional type. Although Th17/Tc17 cells are apparently distinct from the Th1/IFN-γ-producing CD8 + T (Tc1) cell lineage, recent reports have revealed that Th17/Tc17 are highly plastic and can convert to Th1/Tc1-like cells regulated by IL-12 signaling [9][10][11]. Exposure of Th17 cells to IL-12 results in STAT4/T-bet-dependent shutdown of IL-17 expression by rapid chromatin remodeling of the Il17a gene locus, while permitting IFN-γ transcription by histone modulation in the Ifng promoter region [12]. These strictly regulated mechanisms allow T cells to exhibit either type 17 or type 1 responses, and seem to be critical machinery for blocking exaggerated immune responses. This suggests a high...

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Transcription Factor Smad-Independent T Helper 17 Cell Induction by Transforming-Growth Factor-β Is Mediated by Suppression of Eomesodermin

Cited by 123 publications

References 66 publications

Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

Eomesodermin Expression in CD4+ T Cells Restricts Peripheral Foxp3 Induction

TGF‐β in the Immune Response

The development of IL‐17/IFN‐γ‐double producing CTLs from Tc17 cells is driven by epigenetic suppression of Socs3 gene promoter

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