Interleukin-6 produced by enteric neurons regulates the number and phenotype of microbe-responsive regulatory T cells in the gut

Yan, Yiqing; Ramanan, Deepshika; Rozenberg, Milena; McGovern, Kelly; Rastelli, Daniella; Vijaykumar, Brinda; Yaghi, Omar; Voisin, Tiphaine; Mosaheb, Munir M.; Chiu, Isaac M.; Itzkovitz, Shalev; Rao, Meenakshi; Mathis, Diane; Benoist, Christophe

doi:10.1016/j.immuni.2021.02.002

Cited by 80 publications

(66 citation statements)

References 77 publications

(123 reference statements)

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“…However, a subset of pTreg cells that is induced in the gut and co-expresses Foxp3 and ROR-γt to regulate immune responses to commensal bacteria is dependent on IL-6. In fact, Il6 –/– mice exhibit significantly reduced fractions of ROR-γt + Treg cells in the gut lamina propria [54] , and a very recent report suggests that enteric neurons are a relevant source of IL-6 for the induction of ROR-γt + Treg cells [55] . ROR-γt + Treg cells and Th17 cells share similar cytokine cues for their development, yet are differentially dependent on vitamine A, which promotes Treg induction but not Th17 cell development [54] .…”

Section: Sensing Of Il-6 By Treg Cellsmentioning

confidence: 99%

Role of IL-6 in the commitment of T cell subsets

Korn

Hiltensperger

2021

Cytokine

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Section: Sensing Of Il-6 By Treg Cellsmentioning

confidence: 99%

Role of IL-6 in the commitment of T cell subsets

Korn

Hiltensperger

2021

Cytokine

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“…Such potential strategies could include overexpression of FOXP3 as aforementioned, or the knockout of molecules involved in pro-inflammatory signaling pathways present in inflamed tissues of autoimmunity. Notably, although the underlying mechanisms of Treg deficiencies in many AID are not well understood, human studies have reported that cytokines like IL-12 and IL-6 can induce defective Treg functions in vitro (19,134). Hence, ablation of receptors that bind these cytokines might avoid pathological Treg instability following adoptive transfer.…”

Section: Challenges and Improvements Of Antigen-specific Treg Therapiesmentioning

confidence: 99%

Antigen-Specific Regulatory T Cell Therapy in Autoimmune Diseases and Transplantation

Selck

Dominguez‐Villar

2021

Front. Immunol.

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Regulatory T (Treg) cells are a heterogenous population of immunosuppressive T cells whose therapeutic potential for the treatment of autoimmune diseases and graft rejection is currently being explored. While clinical trial results thus far support the safety and efficacy of adoptive therapies using polyclonal Treg cells, some studies suggest that antigen-specific Treg cells are more potent in regulating and improving immune tolerance in a disease-specific manner. Hence, several approaches to generate and/or expand antigen-specific Treg cells in vitro or in vivo are currently under investigation. However, antigen-specific Treg cell therapies face additional challenges that require further consideration, including the identification of disease-relevant antigens as well as the in vivo stability and migratory behavior of Treg cells following transfer. In this review, we discuss these approaches and the potential limitations and describe prospective strategies to enhance the efficacy of antigen-specific Treg cell treatments in autoimmunity and transplantation.

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“…In particular, glial cell-derived neurotrophic factor secreted by EGC is involved in the regulation of ILC3, which are a component of the glial–ILC3–epithelial cell unit that surveys gut environment and control its defence ( 11 ). In a recent study, Yan and co-authors demonstrated that enteric neurons themselves can exert a key role in the regulation of immune cells, by preventing microbial-induced differentiation of regulatory T (Treg) cells through the release of IL-6 ( 12 ).…”

Section: What Is the Gut-brain Axis?mentioning

confidence: 99%

The Gut-Brain Axis in Multiple Sclerosis. Is Its Dysfunction a Pathological Trigger or a Consequence of the Disease?

Parodi

Rosbo

2021

Front. Immunol.

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A large and expending body of evidence indicates that the gut-brain axis likely plays a crucial role in neurological diseases, including multiple sclerosis (MS). As a whole, the gut-brain axis can be considered as a bi-directional multi-crosstalk pathway that governs the interaction between the gut microbiota and the organism. Perturbation in the commensal microbial population, referred to as dysbiosis, is frequently associated with an increased intestinal permeability, or “leaky gut”, which allows the entrance of exogeneous molecules, in particular bacterial products and metabolites, that can disrupt tissue homeostasis and induce inflammation, promoting both local and systemic immune responses. An altered gut microbiota could therefore have significant repercussions not only on immune responses in the gut but also in distal effector immune sites such as the CNS. Indeed, the dysregulation of this bi-directional communication as a consequence of dysbiosis has been implicated as playing a possible role in the pathogenesis of neurological diseases. In multiple sclerosis (MS), the gut-brain axis is increasingly being considered as playing a crucial role in its pathogenesis, with a major focus on specific gut microbiota alterations associated with the disease. In both MS and its purported murine model, experimental autoimmune encephalomyelitis (EAE), gastrointestinal symptoms and/or an altered gut microbiota have been reported together with increased intestinal permeability. In both EAE and MS, specific components of the microbiota have been shown to modulate both effector and regulatory T-cell responses and therefore disease progression, and EAE experiments with germ-free and specific pathogen-free mice transferred with microbiota associated or not with disease have clearly demonstrated the possible role of the microbiota in disease pathogenesis and/or progression. Here, we review the evidence that can point to two possible consequences of the gut-brain axis dysfunction in MS and EAE: 1. A pro-inflammatory intestinal environment and “leaky” gut induced by dysbiosis could lead to an altered communication with the CNS through the cholinergic afferent fibers, thereby contributing to CNS inflammation and disease pathogenesis; and 2. Neuroinflammation affecting efferent cholinergic transmission could result in intestinal inflammation as disease progresses.

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Interleukin-6 produced by enteric neurons regulates the number and phenotype of microbe-responsive regulatory T cells in the gut

Cited by 80 publications

References 77 publications

Role of IL-6 in the commitment of T cell subsets

Role of IL-6 in the commitment of T cell subsets

Antigen-Specific Regulatory T Cell Therapy in Autoimmune Diseases and Transplantation

The Gut-Brain Axis in Multiple Sclerosis. Is Its Dysfunction a Pathological Trigger or a Consequence of the Disease?

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