Regulatory T cells produce profibrotic cytokines in the skin of patients with systemic sclerosis

MacDonald, Katherine G.; Dawson, Nicholas A.J.; Huang, Qing; Dunne, James V.; Levings, Megan K.; Broady, Raewyn

doi:10.1016/j.jaci.2014.12.1932

Cited by 141 publications

(117 citation statements)

References 60 publications

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“…The authors concluded that these FOXP3+ T cells may indeed be Tregs with a functional Th2-like phenotype, which could contribute to enhance a profibrotic response in dermal fibroblasts. Of interest, this study also found that skin-infiltrating FOXP3+ T cells express high levels of the IL-33 receptor ST2 [64] and that the number of IL-13-producing FOXP3+ T cells is increased by culturing SSc skin biopsies in the presence of IL-33. This, together with the fact that only the skin but not peripheral blood FOXP3+ T cells manifested this aberrant Th2-like behavior, further supports the possibility that the skin of SSc patients provides the appropriate environment for transdifferentiation of Tregs (CD4+FOXP3+ T cells) toward a Th2-like phenotype with the consequent amplification of a pro-fibrotic loop.…”

Section: Introductionsupporting

confidence: 51%

“…Skewed X chromosome usage correlates with lower FOXP3 expression in the CD25+ high Treg cells [17]. An intriguing twist to this topic has been brought about by the demonstration that FOXP3-positive cells with high IL-4 and IL-13 production are enriched in the skin of SSc patients compared to normal controls [64]. The authors concluded that these FOXP3+ T cells may indeed be Tregs with a functional Th2-like phenotype, which could contribute to enhance a profibrotic response in dermal fibroblasts.…”

Section: Introductionmentioning

confidence: 99%

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The role of the acquired immune response in systemic sclerosis

Chizzolini

Boin

2015

Semin Immunopathol

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Profound alterations characterize the adaptive immune response in systemic sclerosis, and several layers of evidence support a prominent role exerted by immune cellular effectors and humoral mediators in the pathogenesis of this disease. These include (i) the presence of oligoclonal T cells in tissues undergoing fibrosis consistent with (auto)antigen-specific recruitment, (ii) the preferential expansion of polarized CD4+ and CD8+ T cells producing pro-fibrotic cytokines such as IL-4 and IL-13, (iii) the presence of increased number of cells producing mediators belonging to the IL-17 family, including IL-22, which may drive and participate in inflammatory pathways involving epithelial cells as well as fibroblasts, (iv) the deficient or redirected function of T regulatory cells favoring fibrosis, and (v) the enhanced expression of CD19 and CD21 on naïve B cells, and the upregulation of co-stimulatory molecules in mature B cells, which together with the increased levels of B cell activating factor (BAFF) underlie the propensity to an exaggerated humoral response possibly favoring fibrogenesis. Despite all the progress made in understanding the features of the aberrant immune response in scleroderma, it remains unclear whether the activation of immune effector pathways ultimately drives the disease pathogenesis or rather represents a defective attempt to limit or even reverse excessive extracellular matrix deposition and progressive vasculopathy, the main hallmarks of this disease.

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Section: Introductionsupporting

confidence: 51%

Section: Introductionmentioning

confidence: 99%

The role of the acquired immune response in systemic sclerosis

Chizzolini

Boin

2015

Semin Immunopathol

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“…Treg cells that produce IL-5 and IL-13 were also identified in the skin of patients with systemic sclerosis. 9, 30 Thus, Treg cells may be more plastic than previously predicted, 25 and their functions and phenotypes can be altered depending on their microenvironment. This may explain the apparent paradox in previous clinical studies.…”

Section: Discussionmentioning

confidence: 99%

“…9 In humans, Treg cells that express type 2 cytokines, such as IL-4 and IL-13, were detected in the skin of patients with systemic sclerosis. 30 Thus, Treg cells are likely altered when influenced by certain tissue microenvironments. However, our knowledge about Treg-cell plasticity in allergic airway diseases and their models and regulation of that plasticity is limited.…”

Section: Introductionmentioning

confidence: 99%

IL-33 dysregulates regulatory T cells and impairs established immunologic tolerance in the lungs

Chen

Kobayashi

Izutsu

et al. 2017

Journal of Allergy and Clinical Immunology

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Background Airway exposure to environmental antigens generally leads to immunological tolerance. A fundamental question remains: why is airway tolerance compromised in patients with allergic airway diseases? Interleukin (IL)-33 promotes innate and adaptive type 2 immunity and may provide the answer to this question. Objective The goal of this study was to investigate the roles IL-33 plays in altering regulatory T (Treg) cells in the lungs and in affecting previously established airway immunological tolerance. Methods We analyzed CD4+ forkhead box p3 (Foxp3)+ Treg cells that were isolated from the lungs of naïve BALB/c mice and those treated with IL-33. Airway tolerance and allergen-induced airway inflammation models in mice were used to investigate how IL-33 affects established immunological tolerance in vivo. Results CD4+Foxp3+ Treg cells in the lungs expressed IL-33 receptor ST2. When exposed to IL-33, Treg cells upregulated their expression of canonical Th2 transcription factor GATA3 as well as ST2, and produced type 2 cytokines. Treg cells lost their ability to suppress effector T cells in the presence of IL-33. Airway administration of IL-33 with an antigen impaired the immunological tolerance in the lungs that had been established by prior exposure to the antigen. Dysregulated Foxp3+ Treg cells with distinct characteristics of Th2 cells increased in the lungs of the mice undergoing IL-33-dependent allergen-driven airway inflammation. Conclusions IL-33 dysregulated lung Treg cells and impaired immunological tolerance to inhaled antigens. Established airway tolerance may not be sustained in the presence of an innate immunological stimulation, such as IL-33.

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“…116–118 Treg cells can also undergo reprogramming toward a T H 2-like phenotype based on coexpression of Foxp3 and IL-4 in response to proinflammatory cytokines akin to those expressed in inflamed tissues. 119,120 At the level of gene transcription, miRNAs control the ability for Treg cells to acquire effector functions. This is illustrated by the ability for miR-17 to repress the Treg cell–stabilizing transcription factor Eos while derepressing genes encoding effector cytokines.…”

Section: Heterogeneity Of T Cells and Influence Of The Tissue Microenmentioning

confidence: 99%

Pathogenic CD4 + T cells in patients with asthma

Muehling

Lawrence

Woodfolk

2017

Journal of Allergy and Clinical Immunology

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Asthma encompasses a variety of clinical phenotypes that involve distinct T cell–driven inflammatory processes. Improved understanding of human T-cell biology and the influence of innate cytokines on T-cell responses at the epithelial barrier has led to new asthma paradigms. This review captures recent knowledge on pathogenic CD4+ T cells in asthmatic patients by drawing on observations in mouse models and human disease. In patients with allergic asthma, TH2 cells promote IgE-mediated sensitization, airway hyperreactivity, and eosinophilia. Here we discuss recent discoveries in the myriad molecular pathways that govern the induction of TH2 differentiation and the critical role of GATA-3 in this process. We elaborate on how cross-talk between epithelial cells, dendritic cells, and innate lymphoid cells translates to T-cell outcomes, with an emphasis on the actions of thymic stromal lymphopoietin, IL-25, and IL-33 at the epithelial barrier. New concepts on how T-cell skewing and epitope specificity are shaped by multiple environmental cues integrated by dendritic cell “hubs” are discussed. We also describe advances in understanding the origins of atypical TH2 cells in asthmatic patients, the role of TH1 cells and other non-TH2 types in asthmatic patients, and the features of T-cell pathogenicity at the single-cell level. Progress in technologies that enable highly multiplexed profiling of markers within a single cell promise to overcome barriers to T-cell discovery in human asthmatic patients that could transform our understanding of disease. These developments, along with novel T cell–based therapies, position us to expand the assortment of molecular targets that could facilitate personalized treatments.

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Regulatory T cells produce profibrotic cytokines in the skin of patients with systemic sclerosis

Cited by 141 publications

References 60 publications

The role of the acquired immune response in systemic sclerosis

The role of the acquired immune response in systemic sclerosis

IL-33 dysregulates regulatory T cells and impairs established immunologic tolerance in the lungs

Pathogenic CD4 + T cells in patients with asthma

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