Origin and functions of pro-inflammatory cytokine producing Foxp3+ regulatory T cells

Pandiyan, Pushpa; Zhu, Jinfang

doi:10.1016/j.cyto.2015.07.005

Cited by 107 publications

(86 citation statements)

References 203 publications

(273 reference statements)

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“…While previous reports have suggested that a small subset of T regs produce IFNγ during inflammation (Duhen et al, 2012; Koenecke et al, 2012; Pandiyan and Zhu, 2015), the expression of IFNγ by T regs in tumors and its impact on their suppressive function remains unclear. Using flow cytometry, we found that there was increased expression of IFNγ by Nrp1 −/− T regs in both Nrp1 L/L Foxp3 Cre-YFP/Cre-YFP and Nrp1 L/L Foxp3 Cre-YFP/DTR-GFP mice (Fig.…”

Section: Resultsmentioning

confidence: 95%

Interferon-γ Drives Treg Fragility to Promote Anti-tumor Immunity

Overacre-Delgoffe

Chikina

Dadey

et al. 2017

Cell

426

401

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Summary Regulatory T cells (Tregs) are a barrier to anti-tumor immunity. Neuropilin-1 (Nrp1) is required to maintain intratumoral Treg stability and function but is dispensable for peripheral immune tolerance. Treg-restricted Nrp1 deletion results in profound tumor resistance due to Treg functional fragility. Thus, identifying the basis for Nrp1 dependency and the key drivers of Treg fragility could help to improve immunotherapy for human cancer. We show that a high percentage of intratumoral NRP1+ Tregs correlates with poor prognosis in melanoma and head and neck squamous cell carcinoma. Using a mouse model of melanoma where Nrp1-deficient (Nrp1−/−) and wild-type (Nrp1+/+) Tregs can be assessed in a competitive environment, we find that a high proportion of intratumoral Nrp1−/− Tregs produce interferon-γ (IFNγ), which drives the fragility of surrounding WT Tregs, boosts anti-tumor immunity, and facilitates tumor clearance. We also show that IFNγ-induced Treg fragility is required for response to anti-PD1, suggesting that cancer therapies promoting Treg fragility may be efficacious.

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Section: Resultsmentioning

confidence: 95%

Interferon-γ Drives Treg Fragility to Promote Anti-tumor Immunity

Overacre-Delgoffe

Chikina

Dadey

et al. 2017

Cell

426

401

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“…Recent data has demonstrated that Tregs may suppress inflammation through a host of different cell-contact dependent and cell-contact independent mechanisms. 34,35 As a part of their cell-contact independent suppressive repertoire, Tregs are known to secrete IL-10, TGFβ, IL-35, immunosuppressive purines, and metabolically compete for growth cytokines and metabolites. As part of their cell-contact-dependent suppressive repertoire, Tregs may block DC maturation and self-antigen presentation via negative co-stimulatory molecules, including at least CTLA4, GITR, PD-1, LAG3, Nrp1, and TIGIT.…”

Section: Discussionmentioning

confidence: 99%

Atherosclerosis-Driven Treg Plasticity Results in Formation of a Dysfunctional Subset of Plastic IFNγ ⁺ Th1/Tregs

Butcher

Filipowicz

Waseem

et al. 2016

Circulation Research

138

125

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Rationale Foxp3+ T regulatory cells (Tregs) are key players in maintaining immune homeostasis. Evidence suggests that Tregs respond to environmental cues to permit or suppress inflammation. In atherosclerosis, Th1-driven inflammation affects Treg homeostasis, but the mechanisms governing this phenomenon are unclear. Objective Here, we address whether atherosclerosis impacts Treg plasticity and functionality in Apoe−/− mice, and what effect Treg plasticity might have on the pathology of atherosclerosis. Methods and Results We demonstrate that atherosclerosis promotes Treg plasticity, resulting in the reduction of CXCR3+ Tregs, and the accumulation of an intermediate Th1-like IFNγ+CCR5+ Treg subset (Th1/Tregs) within the aorta. Importantly, Th1/Tregs arise in atherosclerosis from bona fide Tregs, rather than T effector cells. We show that Th1/Tregs recovered from atherosclerotic mice are dysfunctional in suppression assays. Using an adoptive transfer system and plasticity-prone Mir146a−/− Tregs, we demonstrate that elevated IFNγ+ Mir146a−/− Th1/Tregs are unable to adequately reduce atherosclerosis, arterial Th1, or macrophage content within Apoe−/− mice, in comparison to Mir146a+/+ Tregs. Lastly, via single cell RNA-sequencing and RT-PCR we show that Th1/Tregs possess a unique transcriptional phenotype characterized by co-expression of Treg and Th1 lineage genes, and a down-regulation of Treg-related genes, including Ikzf2, Ikzf4, Tigit, Lilrb4, and Il10. Additionally, an ingenuity pathway analysis further implicates IFNγ, IFNα, IL-2, IL-7, CTLA4, T cell receptor, and Csnk2b-related pathways in regulating Treg plasticity. Conclusions Atherosclerosis drives Treg plasticity, resulting in the accumulation of dysfunctional IFNγ+ Th1/Tregs that may permit further arterial inflammation and atherogenesis.

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“…Microorganisms, when captured by cells of innate immunity, induce the production of certain interleukins that will direct the polarization of the TCD4+cells. These interleukins induce the production of transcription factors that will determine specific signaling pathways, which are responsible for the production of interleukins for each of these T cell patterns [2,3].…”

Section: Immune Response Associated To Infectionmentioning

confidence: 99%

Applications and Perspectives of Biosensors for Diagnostics in Infectious Diseases

Etchegaray¹

2018

CJMI

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Infectious diseases are considered a major cause of morbidity and/or mortality worldwide, despite the development of preventive and control strategies. Infectious diseases result from the invasion of body tissues by disease-causing microorganisms. The occurrence and development of infectious diseases are closely associated with the functional state of the immune system. Interleukins play significant roles in modulating the immune response of the host during the course of an infectious disease, contributing to the maintenance of the homeostasis of the immune system. The use of biosensors for the detection of interleukins is a new and important strategy for the diagnosis of the infection and the immunological response profile that occurs for specific diseases, thus helping in the effective diagnosis, and allowing physicians to design treatment in a faster way, which contributes to better prognosis. For example, in the oral environment there are two major infectious diseases: caries and periodontitis. The microbes involved are respectively, Streptococcus mutans and Porphyromonasgingivalis. The presence of specific interleukins in saliva or crevicular fluid will indicate that there is potentially an infectious disease, which could be connected with either caries or periodontal disease. For instance, an indicative for caries could be the presence of IL-6 in saliva, while periodontal disease would be confirmed by the presence of IL-17 in crevicular fluid. In addition, both diseases could be confirmed by the detection of higher levels of each of one of the pathogens. Considering the development of biosensor design and construction, the answer to all these question could be obtained in a single analysis.

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Origin and functions of pro-inflammatory cytokine producing Foxp3+ regulatory T cells

Cited by 107 publications

References 203 publications

Interferon-γ Drives Treg Fragility to Promote Anti-tumor Immunity

Interferon-γ Drives Treg Fragility to Promote Anti-tumor Immunity

Atherosclerosis-Driven Treg Plasticity Results in Formation of a Dysfunctional Subset of Plastic IFNγ ⁺ Th1/Tregs

Applications and Perspectives of Biosensors for Diagnostics in Infectious Diseases

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Origin and functions of pro-inflammatory cytokine producing Foxp3+ regulatory T cells

Cited by 107 publications

References 203 publications

Interferon-γ Drives Treg Fragility to Promote Anti-tumor Immunity

Interferon-γ Drives Treg Fragility to Promote Anti-tumor Immunity

Atherosclerosis-Driven Treg Plasticity Results in Formation of a Dysfunctional Subset of Plastic IFNγ + Th1/Tregs

Applications and Perspectives of Biosensors for Diagnostics in Infectious Diseases

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Atherosclerosis-Driven Treg Plasticity Results in Formation of a Dysfunctional Subset of Plastic IFNγ ⁺ Th1/Tregs