<i>Eomes</i> controls the development of Th17‐derived (non‐classic) Th1 cells during chronic inflammation

Mazzoni, Alessio; Maggi, Laura; Siracusa, Francesco; Ramazzotti, Matteo; Rossi, Maria Caterina; Santarlasci, Veronica; Montaini, Gianni; Capone, Manuela; Rossettini, Beatrice; Palma, Raffaele De; Kruglov, Andrey; Chang, Hyun‐Dong; Cimaz, Rolando; Maggi, Enrico; Romagnani, Sergio; Liotta, Francesco; Cosmi, Lorenzo; Annunziato, Francesco

doi:10.1002/eji.201847677

Cited by 60 publications

(82 citation statements)

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“…Th1 cells are traditionally considered a highly stable cell subset. Indeed, we and others have shown that Th1 cells (either classic or non‐classic) are resistant to the activity of pro‐Th17 cytokines . Only ROR‐ γ t forced expression by way of lentiviral vector can trigger IL‐17 production by Th1 cells .…”

Section: Plasticity Of Th17 Cellsmentioning

confidence: 91%

“…In parallel, non‐classic Th1 cells acquire Th1 features such as expression of the chemokine receptor CXCR3 and of the transcription factor Tbet . Non‐classic Th1 cells produce IFN‐ γ and granulocyte–macrophage colony‐stimulating factor (GM‐CSF) as classic Th1 cells do . More recently we showed that also tumor necrosis factor‐ α (TNF‐ α ) can promote the development of non‐classic Th1 cells from Th17 cells .…”

Section: Plasticity Of Th17 Cellsmentioning

confidence: 99%

“…In agreement with this, we have shown that human Th1 cells express the transcription factor Eomes, which selectively inhibits the expression of RORC2 and IL17A . Of note, Eomes is expressed also by non‐classic Th1 cells, which suggests that the differentiation of Th17 cells into Th1 is irreversible, at least until the molecular machinery that stabilizes the Th1 phenotype is expressed . For this reason, the development of non‐classic Th1 cells from Th17 is tightly controlled.…”

Section: Plasticity Of Th17 Cellsmentioning

confidence: 99%

“…43 Non-classic Th1 cells produce IFN-c and granulocyte-macrophage colony-stimulating factor (GM-CSF) as classic Th1 cells do. 44 More recently we showed that also tumor necrosis factor-a (TNF-a) can promote the development of non-classic Th1 cells from Th17 cells. 45 In addition to these data demonstrating the plasticity of human Th17 cells, similar findings have been obtained in mouse.…”

Section: Plasticity Of Th17 Cellsmentioning

confidence: 99%

“…Indeed, we and others have shown that Th1 cells (either classic or non-classic) are resistant to the activity of pro-Th17 cytokines. 44,54 Only ROR-ct forced expression by way of lentiviral vector can trigger IL-17 production by Th1 cells. 44,54 Supporting this notion, it has been shown that several molecular mechanisms stabilize the Th1 phenotype and restrain the expression of Th17 genes.…”

Section: Plasticity Of Th17 Cellsmentioning

confidence: 99%

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Biological and clinical significance of T helper 17 cell plasticity

et al. 2019

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Mature T helper (Th) effector cells originate following antigen recognition by naive T precursors. The maturation process is accompanied by the acquisition of specific effector functions that distinguish at least three different T helper subsets: Th1, Th2 and Th17. In general, maturation of somatic cells is accompanied by terminal differentiation. However, accumulating evidence shows that effector T cells retain a certain degree of plasticity. This is especially true for Th17 cells, which have been shown to converge towards other phenotypes in response to specific microenvironmental pressure. In this review we will discuss the experimental evidence that supports the hypothesis of Th17 plasticity, with particular emphasis on the generation of Th17‐derived ‘non‐classic’ Th1 cells, and the molecular networks that control it. Moreover, we will consider why Th17 plasticity is important for host protection, but also why it can have pathogenic functions during chronic inflammation. Regarding the last point, we will discuss a possible role for biological drugs in the control of Th17 plasticity and disease course.

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Section: Plasticity Of Th17 Cellsmentioning

confidence: 91%

Section: Plasticity Of Th17 Cellsmentioning

confidence: 99%

Section: Plasticity Of Th17 Cellsmentioning

confidence: 99%

Section: Plasticity Of Th17 Cellsmentioning

confidence: 99%

Section: Plasticity Of Th17 Cellsmentioning

confidence: 99%

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Biological and clinical significance of T helper 17 cell plasticity

et al. 2019

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Eomesodermin controls a unique differentiation program in human IL‐10 and IFN‐γ coproducing regulatory T cells

et al. 2018

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Whether human IL-10-producing regulatory T cells ("Tr1") represent a distinct differentiation lineage or an unstable activation stage remains a key unsolved issue. Here, we report that Eomesodermin (Eomes) acted as a lineage-defining transcription factor in human IFN-γ/IL-10 coproducing Tr1-like cells. In vivo occurring Tr1-like cells expressed Eomes, and were clearly distinct from all other CD4 + T-cell subsets, including conventional cytotoxic CD4 + T cells. They expressed Granzyme (Gzm) K, but had lost CD40L and IL-7R expression. Eomes antagonized the Th17 fate, and directly controlled IFN-γ and GzmK expression. However, Eomes binding to the IL-10 promoter was not detectable in human CD4 + T cells, presumably because critical Tbox binding sites of the mouse were not conserved. A precommitment to a Tr1-like fate, i.e. concominant induction of Eomes, GzmK, and IFN-γ, was promoted by IL-4 and IL-12-secreting myeloid dendritic cells. Consistently, Th1 effector memory cells contained precommitted Eomes + GzmK + T cells. Stimulation with T-cell receptor (TCR) agonists and IL-27 promoted the generation of Tr1-like effector cells by inducing switching from CD40L to IL-10. Importantly, CD4 + Eomes + T-cell subsets were present in lymphoid and nonlymphoid tissues, and their frequencies varied systemically in patients with inflammatory bowel disease and graft-versus-host disease. We propose that Eomes + Tr1-like cells are effector cells of a unique GzmK-expressing CD4 + T-cell subset.

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The role of Eomes in human CD4 T cell differentiation: A question of context

2019

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Eomesodermin (Eomes) is a transcription factor (TF) of the T-box family closely related to T-bet known for its role in CD8 T cell and natural killer cell differentiation. However, the role of Eomes in CD4 T-cell differentiation is less well appreciated. In this issue of the European Journal of Immunology[Eur. J. Immunol. 2019. 49: 79-95] Mazzoni et al. and [Eur. J. Immunol. 2019. 49: 96-111] Gruarin et al. studied the role of Eomes in human CD4 T-cell differentiation. Mazzoni et al. showed that Eomes plays a key role in helper T cell (Th) plasticity by favoring the phenotype shift of Th17 cells toward non-classic Th1 cells; while Gruarin et al. proposed Eomes as a lineage-defining TF for human IL-10 and IFN-γ co-producing regulatory T-cells (Tr1 cells). Both studies show that Eomes drives IFN-γ secretion and stamps a "cytotoxic" signature, while it also represses Th17 features. However, additional signals including the cytokine milieu may further influence the fate of Eomes + CD4 T cells. A common feature of Eomes + CD4 T cells appears to be their accumulation in inflamed tissues in patients with chronic inflammatory disorders. Whether Eomes favors expression of the proinflammatory cytokines or on the contrary, promotes the anti-inflammatory cytokines, remains a matter of debate.Keywords: EOMES r CD4 T cells r Regulatory T cells r Th1 r Th17 See accompanying articles by Mazzoni et al. and Gruarin et al.CD4 T cells can adopt different functional fates depending on the set of transcription factors (TF) they express, these TF being induced by various polarizing cytokines. Th1, Th2 and Th17 helper lineages are defined by expression of T-bet, Gata-3 and RORγt expression, respectively. Helper CD4 T cell subsets are also known to be highly plastic, especially the Th17 type. Th1 cells can derive directly from naïve CD4 T cells or from differentiated Th17 cells.

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Eomes controls the development of Th17‐derived (non‐classic) Th1 cells during chronic inflammation

Cited by 60 publications

References 50 publications

Biological and clinical significance of T helper 17 cell plasticity

Biological and clinical significance of T helper 17 cell plasticity

Eomesodermin controls a unique differentiation program in human IL‐10 and IFN‐γ coproducing regulatory T cells

The role of Eomes in human CD4 T cell differentiation: A question of context

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