Immune quiescence in the oral mucosa is maintained by a uniquely large population of highly activated Foxp3+ regulatory T cells

Park, Jooyoung; Chung, Hwa‐Jin; DiPalma, Devon; Tai, Xuguang; Park, Jung Hyun

doi:10.1038/s41385-018-0027-2

Cited by 38 publications

(30 citation statements)

References 57 publications

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“…Immune suppression might be undetectable at the RNA level as transcriptional changes may occur in rare cell populations that are lost in resolution in the whole tissue. Tregs are more abundant in the oral mucosa compared to other organs (34). Detection of lymphocytes in the tongue is challenging due to the small number of cells and the high degree of autofluorescence of this tissue (37, 38).…”

Section: Resultsmentioning

confidence: 99%

Persistence of Candida albicans in the Oral Mucosa Induces a Curbed Inflammatory Host Response That Is Independent of Immunosuppression

et al. 2019

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Controlled immune activation in response to commensal microbes is critical for the maintenance of stable colonization and prevention of microbial overgrowth on epithelial surfaces. Our understanding of the host mechanisms that regulate bacterial commensalism has increased substantially, however, much less data exist regarding host responses to members of the fungal microbiota on colonized surfaces. Using a murine model of oropharyngeal candidiasis, we have recently shown that differences in immune activation in response to diverse natural isolates of Candida albicans are associated with different outcomes of the host-fungal interaction. Here we applied a genome-wide transcriptomic approach to show that rapid induction of a strong inflammatory response characterized by neutrophil-associated genes upon C. albicans colonization inversely correlated with the ability of the fungus to persist in the oral mucosa. Surprisingly, persistent fungal isolates showed no signs of a compensatory regulatory immune response. By combining RNA-seq data, genetic mouse models, and co-infection experiments, we show that attenuation of the inflammatory response at the onset of infection with a persistent isolate is not a consequence of enhanced immunosuppression. Importantly, depletion of regulatory T cells or deletion of the immunoregulatory cytokine IL-10 did not alter host-protective type 17 immunity nor did it impair fungal survival in the oral mucosa, indicating that persistence of C. albicans in the oral mucosa is not a consequence of suppressed antifungal immunity.

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Section: Resultsmentioning

confidence: 99%

Persistence of Candida albicans in the Oral Mucosa Induces a Curbed Inflammatory Host Response That Is Independent of Immunosuppression

et al. 2019

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“…CD4 + CD25 + Foxp3 + regulatory T cells (T regs ) are central in controlling the magnitude of an immune response thereby regulating autoimmunity and maintaining mucosal tolerance (1). We and others have shown that 5%-10% of CD4 + T cells have a T reg phenotype in normal oral mucosa (2)(3)(4). Molecular components that define their functional plasticity and heterogeneity are not completely characterized during mucosal infections, and appear to be driven by specific stimulation and cytokine milieu.…”

Section: Introductionmentioning

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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“…Accordingly, recent studies reveal that Foxp3+ Tregs are involved in regulating immunity of the oral mucosa, where a unique Treg population is found highly enriched and could be phenotypically distinguished from those in secondary lymphoid organs. 82 Particularly, this Treg population is found abound with a high level of tissue-resident marker CD103 and costimulatory factor CTLA4. Correspondingly, Foxp3+ Treg ablation resulted in striking activated effector T-cell infiltration in oral mucosa, leading to local tissue destruction.…”

Section: Mucosamentioning

confidence: 99%

“…However, intriguingly, inflammation is rarely occurred in the oral cavity, which indicates the overt activation of immune response might be dynamically suppressed. Accordingly, recent studies reveal that Foxp3+ Tregs are involved in regulating immunity of the oral mucosa, where a unique Treg population is found highly enriched and could be phenotypically distinguished from those in secondary lymphoid organs . Particularly, this Treg population is found abound with a high level of tissue‐resident marker CD103 and costimulatory factor CTLA4.…”

Section: The Development and Functions Of Tissue‐resident Tregsmentioning

confidence: 99%

Metabolic adaptation orchestrates tissue context‐dependent behavior in regulatory T cells

Wang

2020

Immunological Reviews

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Immunological Reviews. 2020;295:126-139. wileyonlinelibrary.com/journal/imr | INTRODUC TI ONThe immune system is mainly responsible for protecting individuals from pathogen invasion. Meanwhile, the immune system also actively participates in tissue repairing and homeostasis, which are critical for the avoidance of autoimmunity. A subset of CD4 + T cells, which is characterized by the expression of the master transcription factor forkhead box protein P3 (Foxp3) and known as regulatory T cells (Tregs), is the major immune subset to maintain the immune homeostasis. 1-4 The importance of Tregs on governing peripheral tissue and immune homeostasis is validated by observations in both human patients and murine models. In humans, the mutations in Foxp3 result in impaired development and dysfunction of Tregs and cause immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome, characterized by multiple autoimmune disorders. 5,6 Mice carrying dysfunctional Foxp3, known as scurfy mice, are deficient in Abstract The diverse distribution and functions of regulatory T cells (Tregs) ensure tissue and immune homeostasis; however, it remains unclear which factors can guide distribution, local differentiation, and tissue context-specific behavior in Tregs. Although the emerging concept that Tregs could re-adjust their transcriptome based on their habitations is supported by recent findings, the underlying mechanisms that reprogram transcriptome in Tregs are unknown. In the past decade, metabolic machineries have been revealed as a new regulatory circuit, known as immunometabolic regulation, to orchestrate activation, differentiation, and functions in a variety of immune cells, including Tregs. Given that systemic and local alterations of nutrient availability and metabolite profile associate with perturbation of Treg abundance and functions, it highlights that immunometabolic regulation may be one of the mechanisms that orchestrate tissue context-specific regulation in Tregs. The understanding on how metabolic program instructs Tregs in peripheral tissues not only represents a critical opportunity to delineate a new avenue in Treg biology but also provides a unique window to harness Treg-targeting approaches for treating cancer and autoimmunity with minimizing side effects. This review will highlight the metabolic features on guiding Treg formation and function in a disease-oriented perspective and aim to pave the foundation for future studies. K E Y W O R D S autoimmunity, cancer, immunometabolism, inflammation, metabolic adaptation, regulatory T cell | 127 WANG et Al.

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Immune quiescence in the oral mucosa is maintained by a uniquely large population of highly activated Foxp3+ regulatory T cells

Cited by 38 publications

References 57 publications

Persistence of Candida albicans in the Oral Mucosa Induces a Curbed Inflammatory Host Response That Is Independent of Immunosuppression

Persistence of Candida albicans in the Oral Mucosa Induces a Curbed Inflammatory Host Response That Is Independent of Immunosuppression

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

Metabolic adaptation orchestrates tissue context‐dependent behavior in regulatory T cells

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