T cell‐mediated induction of thymic stromal lymphopoietin in differentiated human primary bronchial epithelial cells

Hui, Claudia C.K.; Murphy, D.M.; Neighbour, Helen; Al-Sayegh, Mohamed; O'Byrne, S.; Thong, Bruce; Denburg, Judah A.; Larché, Mark

doi:10.1111/cea.12330

Cited by 17 publications

(12 citation statements)

References 45 publications

(100 reference statements)

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“…45,49,52 TSLP also acts directly on T H 2 cells (Fig 2). TSLP receptor is preferentially expressed on dividing human T H 2 cells isolated from allergic subjects 53 and on skin-homing T H 2 cells (CLA + CCR4 + CXCR3 − ) in patients with AD.…”

Section: Tslpmentioning

confidence: 87%

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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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Section: Tslpmentioning

confidence: 87%

“…T H 2 cells also positively feedback on epithelial cells in the allergic host to enhance their production of TSLP. 52 Interestingly, these effects are principally mediated by IL-1β, IL-6, and CXCL8 as opposed to T H 2 cytokines themselves.…”

Section: Tslpmentioning

confidence: 99%

Pathogenic CD4 + T cells in patients with asthma

Muehling

Lawrence

Woodfolk

2017

Journal of Allergy and Clinical Immunology

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“…Recent studies showed that Th2 cytokines released from antigen-specific T cells could enhance the secretions of epithelial TSLP and production of CCL17 in DCs to augment inflammation. 40 In addition, Th2 cytokines could abrogate TSLP-mediated induction of CCR7, which plays a key role in the migration of DCs from inflamed tissues to the draining lymph nodes and retain active DCs in the inflamed tissue to further exacerbate local inflammation. 41 Furthermore, TSLP signaling in CD4 + T cells was required for the Th2 memory formation and recall response to local antigen challenges.…”

Section: Discussionmentioning

confidence: 99%

Targeting TSLP With shRNA Alleviates Airway Inflammation and Decreases Epithelial CCL17 in a Murine Model of Asthma

Chen

Chiang

2016

Molecular Therapy - Nucleic Acids

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Airway epithelium defends the invasion from microorganisms and regulates immune responses in allergic asthma. Thymic stromal lymphopoietin (TSLP) from inflamed epithelium promotes maturation of dendritic cells (DCs) to prime Th2 responses via CCL17, which induces chemotaxis of CD4+ T cells to mediate inflammation. However, few studies have investigated the regulation of epithelial CCL17. In this study, we used shRNA against TSLP to clarify the role of TSLP in the airway inflammation and whether TSLP affects the airway inflammation via epithelial CCL17. Specific shTSLP was delivered by lentivirus and selected by the knockdown efficiency. Allergic mice were intratracheally pretreated with the lentivirus and followed by intranasal ovalbumin (OVA) challenges. The sera antibody levels, airway inflammation, airway hyper-responsiveness (AHR), cytokine levels in bronchoalveolar lavage fluids, and CCL17 expressions in lungs were determined. In vivo, TSLP attenuation reduced the AHR, decreased the airway inflammation, inhibited the maturations of DCs, and suppressed the migration of T cells. Furthermore, the expression of CCL17 was particularly decreased in bronchial epithelium. In vitro, CCL17 induction was regulated by TSLP. In conclusion, TSLP might coordinate airway inflammation partially via CCL17-mediated responses and this study provides the vital utility of TSLP to develop the therapeutic approach in allergic airway inflammation.

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“…Challenge of cultured epithelial cells from asthmatic donors with double-stranded RNA results in a skewed response favoring more TSLP and less type 1 interferon compared with healthy cells 128 . Allergen-specific T cells also enhance TSLP production by epithelial cells from asthmatic donors, suggesting that T cell–airway epithelium interactions can lead to maintenance and amplification of allergic inflammation 129 . In a double-blind, placebo-controlled study, treatment with a human mAb to TSLP resolved airway inflammation and attenuated allergen-induced bronchoconstriction, findings consistent with TSLP as a therapeutic target in patients with allergic asthma 130 .…”

Section: Dysregulation Of the Epithelial Barrier In Asthmatic Patientsmentioning

confidence: 99%

Phenotypic and genetic aspects of epithelial barrier function in asthmatic patients

Loxham

Davies

2017

Journal of Allergy and Clinical Immunology

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The bronchial epithelium is continuously exposed to a multitude of noxious challenges in inhaled air. Cellular contact with most damaging agents is reduced by the action of the mucociliary apparatus and by formation of a physical barrier that controls passage of ions and macromolecules. In conjunction with these defensive barrier functions, immunomodulatory cross-talk between the bronchial epithelium and tissue-resident immune cells controls the tissue microenvironment and barrier homeostasis. This is achieved by expression of an array of sensors that detect a wide variety of viral, bacterial, and nonmicrobial (toxins and irritants) agents, resulting in production of many different soluble and cell-surface molecules that signal to cells of the immune system. The ability of the bronchial epithelium to control the balance of inhibitory and activating signals is essential for orchestrating appropriate inflammatory and immune responses and for temporally modulating these responses to limit tissue injury and control the resolution of inflammation during tissue repair. In asthmatic patients abnormalities in many aspects of epithelial barrier function have been identified. We postulate that such abnormalities play a causal role in immune dysregulation in the airways by translating gene-environment interactions that underpin disease pathogenesis and exacerbation.

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T cell‐mediated induction of thymic stromal lymphopoietin in differentiated human primary bronchial epithelial cells

Cited by 17 publications

References 45 publications

Pathogenic CD4 + T cells in patients with asthma

Pathogenic CD4 + T cells in patients with asthma

Targeting TSLP With shRNA Alleviates Airway Inflammation and Decreases Epithelial CCL17 in a Murine Model of Asthma

Phenotypic and genetic aspects of epithelial barrier function in asthmatic patients

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