IL-1R1 is expressed on both Helios+ and Helios−FoxP3+CD4+ T cells in the rheumatic joint

Müller, Malin; Herrath, Jessica; Malmström, Vivianne

doi:10.1111/cei.12668

Cited by 14 publications

(10 citation statements)

References 50 publications

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“…Previous studies have showed that Helios - but not Helios + human FOXP3 Tregs produce a variety of cytokines ex vivo , including the anti-inflammatory cytokine IL-10 ( 39 , 40 ). Therefore, we next examined the ability of human AdipoR1 + and AdipoR1 - Treg subsets to produce IL-10.…”

Section: Resultsmentioning

confidence: 99%

Adiponectin/AdipoR1 Axis Promotes IL-10 Release by Human Regulatory T Cells

et al. 2021

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BackgroundAdiponectin is an important immunomodulatory mediator in inflammatory conditions. While we previously showed that adiponectin receptor 1 (AdipoR1) is expressed in murine regulatory T cells (Tregs), its expression in human Tregs remain unknown. Here, we examined the expression of AdipoR1 in human Tregs and whether its ligand, globular adiponectin (gAd) affects the Treg ability to secrete IL-10 and the role of Type 2 (T2) inflammation in such process.MethodsHuman Tregs from peripheral blood were analyzed by flow cytometry for AdipoR1, Helios and IL-10 expression. CD4+ T cells enriched from peripheral blood mononuclear cells (PBMCs) were cultured in the presence or the absence of gAd or the chemical adiponectin receptor agonist, AdipoRon, or in a T2 cytokine milieu. Flow cytometry was then used to assess intracellular IL-10, IL-10 secreting cells, FOXP3 and Helios expression, and phosphorylated p38 MAP kinase (MAPK). IL-10 levels in CD4+ T cell supernatants were quantified by ELISA.ResultsWe found that a subset of human Tregs expressed AdipoR1. Importantly, more Helios- cells expressed AdipoR1 than Helios+ cells. Likewise, there was a higher frequency of IL-10+ cells within Helios- AdipoR1+ Tregs compared to Helios+ AdipoR1+ Tregs. In contrast, the IL-10 mean fluorescence intensity (MFI) was higher in Helios+ AdipoR1+ Tregs compared to Helios-AdipoR1+ Tregs. When human CD4+ T cells were treated with gAd or AdipoRon, a significant increase in IL-10 secretion, FOXP3 expression, and p38 MAPK phosphorylation was observed in Helios- AdipoR1+ Tregs. Interestingly, gAd under T2 cytokine milieu significantly increased the intracellular levels of IL-10, mainly in Helios+ AdipoR1+ Tregs, and IL-10 levels in supernatants of CD4+ T cells.ConclusionsCollectively, our findings suggest that adiponectin/AdipoR1 axis promotes IL-10 release by Tregs, mainly in Helios- Tregs, and the effect was amplified by T2 inflammation in Helios+ Tregs.

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Section: Resultsmentioning

confidence: 99%

Adiponectin/AdipoR1 Axis Promotes IL-10 Release by Human Regulatory T Cells

et al. 2021

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“…Since IL-1R family members signal through MyD88 (34), MFYcre T regs must lack the ability to signal through cytokines such as IL-1b and IL-33 produced by APC and other cells in the milieu. These cytokines have been previously shown to impact mucosal and tissue T regs (35,36). Therefore, we tested the effects of IL-1b and IL-33 on T reg proliferation.…”

Section: Loss Of Myd88 In Foxp3 + Cells Reduces T Reg Accumulation Inmentioning

confidence: 99%

IL-1β-MyD88-mTOR Axis Promotes Immune-Protective IL-17A+Foxp3+ Cells During Mucosal Infection and Is Dysregulated With Aging

et al. 2020

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CD4 + Foxp3 + T regs maintain immune homeostasis, but distinct mechanisms underlying their functional heterogeneity during infections are driven by specific cytokine milieu. Here we show that MyD88 deletion in Foxp3 + cells altered their function and resulted in increased fungal burden and immunopathology during oral Candida albicans (CA) challenge. Excessive inflammation due to the absence of MyD88 in T regs coincided with a reduction of the unique population of IL-17A expressing Foxp3 + cells (T reg 17) and an increase in dysfunctional IFN-g + /Foxp3 + cells (T reg IFN-g) in infected mice. Failure of MyD88-/-T regs to regulate effector CD4 + T cell functions correlated with heightened levels of IFN-g in CD4 + T cells, as well as increased infiltration of inflammatory monocytes and neutrophils in oral mucosa in vivo. Mechanistically, IL-1b/MyD88 signaling was required for the activation of IRAK-4, Akt, and mTOR, which led to the induction and proliferation of T reg 17 cells. In the absence of IL-1 receptor signaling, T reg 17 cells were reduced, but IL-6-driven expansion of T reg IFN-g cells was increased. This mechanism was physiologically relevant during Candida infection in aged mice, as they exhibited IL-1 receptor/MyD88 defect in Foxp3 + cells, loss of p-mTOR high T reg 17 cells and reduced levels of IL-1b in oral mucosa, which coincided with persistent tongue inflammation. Concurrent with T reg dysfunction, aging was associated with increased CD4 + T cell hyperactivation and heightened levels of IL-6 in mice and humans in oral mucosa in vivo. Taken together, our data identify IL-1b/MyD88/T reg axis as a new component that modulates inflammatory responses in oral mucosa. Also, dysregulation of this axis in an aging immune system may skew host defense towards an immunopathological response in mucosal compartments.

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“…In addition, both IL-1R1 and IL-1R2 are induced on human Tregs after TCR signaling [ 281 ]. Moreover, in the context of rheumatoid arthritis, IL-1R1 is expressed on tissue-activated Tregs [ 282 ]. Recently, in mice, Th17 polarizing conditions have been shown to favor IL-1R1 expression by Tregs.…”

Section: Treg Stabilizationmentioning

confidence: 99%

Recruitment and Expansion of Tregs Cells in the Tumor Environment—How to Target Them?

Cinier

Hubert

Besson

et al. 2021

Cancers

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Regulatory T cells (Tregs) are present in a large majority of solid tumors and are mainly associated with a poor prognosis, as their major function is to inhibit the antitumor immune response contributing to immunosuppression. In this review, we will investigate the mechanisms involved in the recruitment, amplification and stability of Tregs in the tumor microenvironment (TME). We will also review the strategies currently developed to inhibit Tregs’ deleterious impact in the TME by either inhibiting their recruitment, blocking their expansion, favoring their plastic transformation into other CD4+ T-cell subsets, blocking their suppressive function or depleting them specifically in the TME to avoid severe deleterious effects associated with Treg neutralization/depletion in the periphery and normal tissues.

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IL-1R1 is expressed on both Helios+ and Helios−FoxP3+CD4+ T cells in the rheumatic joint

Cited by 14 publications

References 50 publications

Adiponectin/AdipoR1 Axis Promotes IL-10 Release by Human Regulatory T Cells

Adiponectin/AdipoR1 Axis Promotes IL-10 Release by Human Regulatory T Cells

IL-1β-MyD88-mTOR Axis Promotes Immune-Protective IL-17A+Foxp3+ Cells During Mucosal Infection and Is Dysregulated With Aging

Recruitment and Expansion of Tregs Cells in the Tumor Environment—How to Target Them?

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