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Activated T cells secrete extracellular vesicles in the allergic airway that enhance eosinophil viability

ABSTRACT: T cells are not only central orchestrators of immune responses, but they drive tissue pathology in many inflammatory diseases. In allergic asthma, the activation of CD4+ T helper cells in response to allergens drives chronic type 2 lung inflammation characterized by the recruitment of eosinophils. Given the emerging roles of extracellular vesicles (EVs) as mediators of cell-to-cell communication, we hypothesized that T cells would secrete EVs in the lung to regulate the local inflammatory response. Using T cell specific membrane tagging and single vesicle flow cytometry, we found that T cell EVs are secreted into lung lining fluid during allergic inflammation in a mouse model of asthma. Functionally, EVs secreted by polarized T helper type 2 (Th2) cells promote eosinophil survival in vitro. This effect is only seen with EVs collected from Th2 cells activated through the T cell receptor. Activated Th2 cell EVs promote eosinophil survival by a surface-cargo dependent anti-apoptotic mechanism, inducing pro-survival and activation gene expression programs in these target cells. In vivo, activated Th2 cell EVs prolong eosinophilia in the lung after administration into the airways during allergic inflammation. Together, this study adds to emerging literature linking cellular activation state to EV function and supports a role for T cell EVs in enhancing tissue inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE253180 | GEO | 2025/07/03

REPOSITORIES: GEO

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Project description:Memory helper T cells provide long-lasting host defeMemory helper T cells provide long-lasting host defense against microbial pathogens, while distinct subpopulations of memory T cells drive chronic inflammatory diseases such as asthma. Asthma is a chronic allergic inflammatory disease with airway remodeling including fibrotic changes. The immunological mechanisms that induce airway fibrotic changes in allergic inflammation remain unknown. We found that Interleukin-33 (IL-33) enhanced Amphiregulin production by the IL-33 receptor, ST2hi memory T helper-2 (Th2) cells. Amphiregulin-epidermal growth factor receptor (EGFR)-mediated signaling directly reprogramed eosinophils to an inflammatory state with enhanced production of Osteopontin, a key profibrotic immunomodulatory protein. IL-5-producing memory Th2 cells and Amphiregulin-producing memory Th2 cells appeared to cooperate to establish lung fibrosis. The analysis of polyps from patients with eosinophilic chronic rhinosinusitis revealed fibrosis with accumulation of Amphiregulin-producing CRTH2hiCD161hiCD45RO+CD4+ Th2 cells and Osteopontin-producing eosinophils. Thus, the IL-33-Amphiregulin-Osteopontin axis directs fibrotic responses in eosinophilic airway inflammation and is a potential target for the treatment of fibrosis induced by chronic allergic disorders. against microbial pathogens, while distinct subpopulations of memory T cells drive chronic inflammatory diseases such as asthma. Asthma is a chronic allergic inflammatory disease with airway remodeling including fibrotic changes. The immunological mechanisms that induce airway fibrotic changes in allergic inflammation remain unknown. We found that Interleukin-33 (IL-33) enhanced Amphiregulin production by the IL-33 receptor, ST2 hi memory T helper-2 (Th2) cells. Amphiregulin-epidermal growth factor receptor (EGFR)-mediated signaling directly reprogramed eosinophils to an inflammatory state with enhanced production of Osteopontin, a key profibrotic immunomodulatory protein. IL-5-producing memory Th2 cells and Amphiregulin-producing memory Th2 cells appeared to cooperate to establish lung fibrosis. The analysis of polyps from patients with eosinophilic chronic rhinosinusitis revealed fibrosis with accumulation of Amphiregulin-producing CRTH2hiCD161hiCD45RO+CD4+ Th2 cells and Osteopontin-producing eosinophils. Thus, the IL-33-Amphiregulin-Osteopontin axis directs fibrotic responses in eosinophilic airway inflammation and is a potential target for the treatment of fibrosis induced by chronic allergic disorders.

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Activated T cells secrete extracellular vesicles in the allergic airway that enhance eosinophil viability

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