Human memory FOXP3<sup>+</sup>Tregs secrete IL-17 ex vivo and constitutively express the T<sub>H</sub>17 lineage-specific transcription factor RORγt

Ayyoub, Maha; Deknuydt, Florence; Raimbaud, Isabelle; Dousset, Christelle; Lévêque, Lucie; Bioley, Gilles; Valmori, Danila

doi:10.1073/pnas.0900621106

Cited by 274 publications

(245 citation statements)

References 38 publications

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“…The small volume and availability of fresh blood samples from children with T1D limited the experimental design of sorting regulatory T cells in this series of children studied. In a recent report, the IL-17-producing human regulatory T cells differed from conventional Th17 cells and failed to secrete IL-22 (29). Our findings show strong upregulation of IL-22 transcripts in association with IL-17 and RORC2 activation in diabetic children, which does not support, however, the view that the IL-17-positive cells in T1D are IL-17-producing FOXP3-positive regulatory T cells.…”

Section: Discussioncontrasting

confidence: 99%

IL-17 Immunity in Human Type 1 Diabetes

Honkanen

Nieminen

Gao

et al. 2010

The Journal of Immunology

258

210

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Th17 immunity has been shown to regulate autoimmune diabetes in mice. IL-17 neutralization prevented development of diabetes when given postinitiation of insulitis but not earlier, suggesting interference with the effector phase of the disease. Islet-cell Ag-specific Th17 cells converted into IFN-γ–secreting Th1-like cells and caused diabetes in mice recipients. The role of IL-17 in human type 1 diabetes (T1D) is, however, not established. In this study, we show upregulation of Th17 immunity in peripheral blood T cells from children with T1D. This was characterized by increased IL-17 secretion and expression of IL-17, IL-22, and retinoic acid-related orphan receptor C isoform 2, but also FOXP3 transcripts upon T cell activation in vitro. Also, circulating memory CD4 cells from children with T1D showed the same pattern of IL-17, IL-22 and FOXP3 mRNA upregulation, indicating IL-17 pathway activation in vivo. IL-17–positive T cells appeared to be CD4+ cells expressing TCR-αβ and CCR6, and a subpopulation showed coproduction of IFN-γ. Given the Th17 immunity in T1D, we demonstrated that IL-17 had detrimental effects on human islet cells in vitro; it potentiated both inflammatory and proapoptotic responses. Our findings highlight the role of IL-17 immunity in the pathogenesis of human T1D and point to a potential therapeutic strategy.

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Section: Discussioncontrasting

confidence: 99%

IL-17 Immunity in Human Type 1 Diabetes

Honkanen

Nieminen

Gao

et al. 2010

The Journal of Immunology

258

210

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“…So far, NTreg are the only identified subpopulation of naive T cells that constitutively express a lineage-specific transcription factor and are therefore precommitted to differentiation into a specific lineage. Several recent studies, including studies from our group, have documented a close relationship between FOXP3 + Treg and T H 17 lineages (22)(23)(24)(25). We have shown that stimulation of human FOXP3 + Treg in the presence of LPS-activated monocytes and IL-2 converts them into T H 17 cells (22) and have recently identified a subpopulation of memory Treg that coexpress RORγt and secrete high levels of IL-17 ex vivo (24).…”

mentioning

confidence: 65%

Human RORγt ⁺ T _H 17 cells preferentially differentiate from naive FOXP3 ⁺ Treg in the presence of lineage-specific polarizing factors

Valmori

Raffin

Raimbaud

et al. 2010

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

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141

116

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RORγt + T H 17 cells are a proinflammatory CD4 + T-cell population associated with autoimmune tissue injury. In mice, priming of T H 17 requires TGF-β, which alone directs the priming of FOXP3 + regulatory T cells (Treg), in association with inflammatory cytokines. Priming of human T H 17 cells from conventional naive CD4 + T cells under similar conditions, however, has proved difficult to achieve. Here, we report that differentiation of human T H 17 cells preferentially occurs from FOXP3 + naive Treg (NTreg) in the presence of IL-2 and IL-1β and is increased by IL-23 and TGF-β. IL-1β-mediated differentiation correlated with IL-1RI expression in stimulated NTreg and was accompanied by induction of RORγt along with down-regulation of FOXP3. IL-17-secreting cells in NTreg cultures cosecreted TNF-α and IL-2 and contained distinct subpopulations cosecreting or not cosecreting IFN-γ and other T H 17-associated cytokines. Polarized NTreg contained significant subpopulations of CCR6-expressing cells that were highly enriched in IL-17-secreting cells. Finally, analysis of CCR6 expression with respect to that of IL-1RI identified distinct IL-17-secreting subpopulations that had maintained or lost their suppressive functions. Together our results support the concept that priming of human T H 17 from naive CD4 + T cells preferentially takes place from FOXP3 + Treg precursors in the presence of lineage-specific polarizing factors.IL-1 | IL-17 | IL-23 | TGF-β | CD4 T cells

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“…In humans, IL-17-producing Foxp3 þ T cells were identified in peripheral blood as well as in the microenvironments of chronic inflammation and cancer. 23,[45][46][47] Although most of these studies indicated that human Foxp3 þ IL-17 þ cells retain regulatory capacity as long as they express Foxp3, it was suggested that they can foster the expression of proinflammatory cytokines and thus behave as ''inflammatory'' Tregs. 23 In addition, in vitro studies showed that human RORgt þ Th17 cells preferentially differentiate from naïve Foxp3 þ T cells that lose their Foxp3 expression 48 that may eventually lead to conversion into pathogenic Th17 cells under inflammatory conditions.…”

Section: Discussionmentioning

confidence: 99%

Foxp3+ T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation

et al. 2016

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Human memory FOXP3⁺Tregs secrete IL-17 ex vivo and constitutively express the T_H17 lineage-specific transcription factor RORγt

Cited by 274 publications

References 38 publications

IL-17 Immunity in Human Type 1 Diabetes

IL-17 Immunity in Human Type 1 Diabetes

Human RORγt ⁺ T _H 17 cells preferentially differentiate from naive FOXP3 ⁺ Treg in the presence of lineage-specific polarizing factors

Foxp3+ T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation

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Human memory FOXP3+Tregs secrete IL-17 ex vivo and constitutively express the TH17 lineage-specific transcription factor RORγt

Cited by 274 publications

References 38 publications

IL-17 Immunity in Human Type 1 Diabetes

IL-17 Immunity in Human Type 1 Diabetes

Human RORγt + T H 17 cells preferentially differentiate from naive FOXP3 + Treg in the presence of lineage-specific polarizing factors

Foxp3+ T cells expressing RORγt represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation

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Human memory FOXP3⁺Tregs secrete IL-17 ex vivo and constitutively express the T_H17 lineage-specific transcription factor RORγt

Human RORγt ⁺ T _H 17 cells preferentially differentiate from naive FOXP3 ⁺ Treg in the presence of lineage-specific polarizing factors