Microbiome Dependent Regulation of Tregs and Th17 Cells in Mucosa

Pandiyan, Pushpa; Bhaskaran, Natarajan; Zou, Mangge; Schneider, Elizabeth; Jayaraman, Sangeetha; Huehn, Jochen

doi:10.3389/fimmu.2019.00426

Cited by 195 publications

(165 citation statements)

References 292 publications

(245 reference statements)

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“…We hypothesized that ME/CFS patients may also have disruptions within effector T cell subsets resident in mucosal tissues such as Th17 cells, which respond to bacterial infections or microbiota and are also linked to autoimmune diseases (Milner et al, 2010;Pandiyan et al, 2019). To identify Th17 cells we first used CD3, CD4, CD45RO, and CCR6 expression (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Increased Tregs in patients may reflect the disturbance of the Th17 and Th1/Th2 cytokine balance in ME/CFS patients, suggesting a major disruption in homeostatic maintenance of immune responses. Indeed, for example, the balance between Th17 cells and Tregs is also critical in the regulation of inflammation, especially related to the gut and microbiome (Omenetti and Pizarro, 2015;Pandiyan et al, 2019). Remarkably, we found a correlation between Th17 and Treg cells in ME/CFS patients, and found the ratio was even more significantly different in patients compared to controls.…”

Section: Discussionmentioning

confidence: 99%

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Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Karhan

Ravanmehr

et al. 2019

Preprint

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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder of unknown etiology, and diagnosis of the disease is largely based on clinical symptoms. We hypothesized that immunological disruption is the major driver of this disease and analyzed a large cohort of ME/CFS patient or control blood samples for differences in T cell subset frequencies and functions. We found that the ratio of CD4+ to CD8+ T cells and the proportion of CD8+ effector memory T cells were increased, whereas NK cells were reduced in ME/CFS patients younger than 50 years old compared to a healthy control group. Remarkably, major differences were observed in Th1, Th2, Th17 and mucosal-associated invariant T (MAIT) T cell subset functions across all ages of patients compared to healthy subjects. While CCR6+ Th17 cells in ME/CFS secreted less IL-17 compared to controls, their overall frequency was higher. Similarly, MAIT cells from patients secreted lower IFNγ, GranzymeA and IL-17 upon activation. Together, these findings suggest chronic stimulation of these T cell populations in ME/CFS patients. In contrast, the frequency of regulatory T cells (Tregs), which control excessive immune activation, was higher in ME/CFS patients. Finally, using a machine learning algorithm called random forest, we determined that the set of T cell parameters analyzed could identify more than 90% of the subjects in the ME/CFS cohort as patients (93% true positive rate or sensitivity). In conclusion, these multiple and major perturbations or dysfunctions in T cell subsets in ME/CFS patients suggest potential chronic infections or microbiome dysbiosis. These findings also have implications for development of ME/CFS specific immune biomarkers and reveal potential targets for novel therapeutic interventions.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Karhan

Ravanmehr

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…This matters not only in OPC but other oral infections such as periodontal bone loss (95) as well as pulmonary infections (96, 97). Even so, not all studies of OPC have found that IL-17 regulates neutrophil infiltration upon OPC (98); the reason for the discrepancy is unclear, but could possibly relate to effects of different local oral microbiota (99, 100).…”

Section: Discussionmentioning

confidence: 99%

A loss-of-function mutation in IL-17F enhances susceptibility of mice to oropharyngeal candidiasis

Zhou

Monin

Gordon

et al. 2020

Preprint

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2Oropharyngeal candidiasis (OPC) is an opportunistic infection of the oral mucosa caused by the 3 commensal fungus C. albicans. IL-17 receptor signaling is essential to prevent OPC in mice and 4 humans, but the individual roles of its ligands, IL-17A, IL-17F and IL-17AF, are less clear. A 5 homozygous IL-17F deficiency in mice does not cause OPC susceptibility, whereas mice lacking 6 IL-17A are moderately susceptible. In humans, a rare heterozygous mutation in IL-17F (IL-7 17F.S65L) was identified that causes chronic mucocutaneous candidiasis, suggesting the existence 8 of essential antifungal pathways mediated by IL-17F and/or IL-17AF. To investigate the role of 9

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“…Moreover, metformin treatment was shown to decrease the frequency of pathogenic Th17 cells and increase the frequency of regulatory T cells (Tregs), thus reducing inflammation in diabetes or IBD murine models [55,56]. Gut dysbiosis and low SCFA production were associated with lower frequency of mucosal Tregs in mice and humans [57]. Bhaskaran et al demonstrated that Tregs were essential in the anti-inflammatory effect of gut-derived SCFA in mice [58].…”

Section: More Than Meets the Eye: Metformin And Gut Microbiota Modifimentioning

confidence: 99%

Metformin effect on gut microbiota: insights for HIV-related inflammation

et al. 2020

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The gut microbiota is emerging as a prominent player in maintaining health through several metabolic and immune pathways. Dysregulation of gut microbiota composition, also known as dysbiosis, is involved in the clinical outcome of diabetes, inflammatory bowel diseases, cancer, aging and HIV infection. Gut dysbiosis and inflammation persist in people living with HIV (PLWH) despite receiving antiretroviral therapy, further contributing to non-AIDS comorbidities. Metformin, a widely used antidiabetic agent, has been found to benefit microbiota composition, promote gut barrier integrity and reduce inflammation in human and animal models of diabetes. Inspired by the effect of metformin on diabetes-related gut dysbiosis, we herein critically review the relevance of metformin to control inflammation in PLWH. Metformin may improve gut microbiota composition, in turn reducing inflammation and risk of non-AIDS comorbidities. This review will pave the way towards innovative strategies to counteract dysregulated microbiota and improve the lives of PLWH.

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Microbiome Dependent Regulation of Tregs and Th17 Cells in Mucosa

Cited by 195 publications

References 292 publications

Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Perturbation of effector and regulatory T cell subsets in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

A loss-of-function mutation in IL-17F enhances susceptibility of mice to oropharyngeal candidiasis

Metformin effect on gut microbiota: insights for HIV-related inflammation

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