Developmental plasticity of Th17 and Treg cells

Lee, Yun Kyung; Mukasa, Ryuta; Hatton, Robin D.; Weaver, Casey T.

doi:10.1016/j.coi.2009.05.021

Cited by 368 publications

(306 citation statements)

References 42 publications

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“…We did not confirm the upregulation of IL-1b and IL-6 transcripts in the resting monocytes from patients with T1D (Fig. 4, Table II) as reported by others (6). However, the patients with T1D also included adults in the study by Bradshaw and coauthors (7), whereas we studied children.…”

Section: No Evidence Of Enhanced Activation Of Il-6 and Il-1b In Monocontrasting

confidence: 51%

“…Indeed, Th17 immunity is considered a crucial element in the mucosal immune protection against bacterial and fungal pathogens (6). Its activation is also seen in autoimmune conditions and inflammatory bowel disease (6,12). In autoimmune diabetes, the lymphocytes in the inflamed islets show mucosal homing properties as demonstrated both in animal models and human T1D (13)(14)(15).…”

Section: Discussionmentioning

confidence: 99%

“…CCR6-expressing T lymphocytes show specific recruitment to the mucosal surfaces. Indeed, Th17 immunity is considered a crucial element in the mucosal immune protection against bacterial and fungal pathogens (6). Its activation is also seen in autoimmune conditions and inflammatory bowel disease (6,12).…”

Section: Discussionmentioning

confidence: 99%

“…In humans, the role of Th17 immunity in T1D is not known, whereas the upregulation of the IL-17 response has been associated with other immune-mediated diseases, such as multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease (6). The generation of Th17 cells is induced by the expression of retinoic acid-related orphan receptor C isoform 2 (RORC2) transcription factor, and TGF-b plus IL-21 are key cytokines for the differentiation of human Th17 cells from naive T cells, whereas the inflammatory cytokines IL-1b and IL-6 are involved in Th17 differentiation from memory T cells (6).…”

mentioning

confidence: 99%

“…The generation of Th17 cells is induced by the expression of retinoic acid-related orphan receptor C isoform 2 (RORC2) transcription factor, and TGF-b plus IL-21 are key cytokines for the differentiation of human Th17 cells from naive T cells, whereas the inflammatory cytokines IL-1b and IL-6 are involved in Th17 differentiation from memory T cells (6). A role for Th17 immunity in human T1D was indirectly suggested by a recent report in which IL-1-and IL-6-secreting monocytes from diabetic patients induced IL-17 production from allogenic memory T cells in vitro (7).…”

mentioning

confidence: 99%

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IL-17 Immunity in Human Type 1 Diabetes

Honkanen

Nieminen

Gao

et al. 2010

The Journal of Immunology

268

214

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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: No Evidence Of Enhanced Activation Of Il-6 and Il-1b In Monocontrasting

confidence: 51%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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IL-17 Immunity in Human Type 1 Diabetes

Honkanen

Nieminen

Gao

et al. 2010

The Journal of Immunology

268

214

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Immune System

Rieber

Haselbeck²

2012

Biochemical Pathways

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Human tumor‐infiltrating Th17 cells have the capacity to differentiate into IFN‐γ⁺ and FOXP3⁺ T cells with potent suppressive function

Hsueh

et al. 2011

Eur J Immunol

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Accumulating evidence suggests that Th17 cells and Tregs may exhibit development plasticity and that CD41 Tregs can differentiate into IL-17-producing T cells; however, whether Th17 cells can reciprocally convert into Tregs has not been described. In this study, we generated Th17 clones from tumor-infiltrating T lymphocytes (TILs). We showed that Th17 clones generated from TILs can differentiate into IFN-c-producing and FOXP3 1 cells after in vitro stimulation with OKT3 and allogeneic peripheral blood mononuclear cells. We further demonstrated that T-cell receptor (TCR) engagement was responsible for this conversion, and that this differentiation was due to the epigenetic modification and reprogramming of gene expression profiles, including lineage-specific transcriptional factor and cytokine genes. In addition to expressing IFN-c and FOXP3, we showed that these differentiated Th17 clones mediated potent suppressive function after repetitive stimulation with OKT3, suggesting that these Th17 clones had differentiated into functional Tregs. We further demonstrated that the Th17-derived Tregs, unlike naturally occurring CD4 1 CD25 1 Tregs, did not reconvert back into Th17 cells even under Th17-biasing cytokine conditions. These results provide the critical evidence that human tumor-infiltrating Th17 cells can differentiate into Tregs and indicate a substantial developmental plasticity of Th17 cells.Keywords: IL-17 . Treg . T-cell development . Th17Supporting Information available online IntroductionRecent discovery of two novel T-cell subsets, Th17 and Tregs, has resulted in an explosion of immunological research that has markedly enhanced our understanding of human T-cell-mediated immunity under both physiological and pathological conditions [1,2]. It is now widely accepted that Tregs have a broad immunosuppressive capacity and play a central role in controlling immune tolerance and homeostasis of the immune system [3,4], whereas Th17 cells are important contributors to the pathogenesis of a wide array of inflammatory and autoimmune diseases [5]. 936that instruct a specific differentiation program [6][7][8]. It is now recognized that cytokines IL-12 and IFN-g are required for the polarization of Th1 cells, whereas signal transducer and activator of transcription 1 and 4 (Stat1 and Stat4) and T box transcription factor (T-bet) are critical for their regulation [6,7]. Th2-cell differentiation requires the cytokine IL-4 and the transcriptional factors GATA3 and Stat6 [6,7]. Th17-cell differentiation is dependent on the transcription factors retinoid-related orphan receptor (RORgt), Stat3 and interferon regulatory factor 4 (IRF-4) [9,10]. TGF-b and IL-6 or TGF-b and IL-21 are critical cytokines for the initiation of mouse Th17-cell differentiation [11][12][13]. Furthermore, IL-23 is critical for the in vivo function of pathogenic effectors of Th17-cells [14,15]. The differentiation and development of Tregs require TGF-b and the forkhead transcription factor, FOXP3 [16].Although different types of T-cell lineages have...

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Developmental plasticity of Th17 and Treg cells

Cited by 368 publications

References 42 publications

IL-17 Immunity in Human Type 1 Diabetes

IL-17 Immunity in Human Type 1 Diabetes

Immune System

Human tumor‐infiltrating Th17 cells have the capacity to differentiate into IFN‐γ⁺ and FOXP3⁺ T cells with potent suppressive function

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Developmental plasticity of Th17 and Treg cells

Cited by 368 publications

References 42 publications

IL-17 Immunity in Human Type 1 Diabetes

IL-17 Immunity in Human Type 1 Diabetes

Immune System

Human tumor‐infiltrating Th17 cells have the capacity to differentiate into IFN‐γ+ and FOXP3+ T cells with potent suppressive function

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Human tumor‐infiltrating Th17 cells have the capacity to differentiate into IFN‐γ⁺ and FOXP3⁺ T cells with potent suppressive function