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DUSP10 constrains innate IL-33-mediated cytokine production in ST2hi memory-type pathogenic Th2 cells

ABSTRACT: Memory CD4+ T helper (Th) cells are crucial for acquired immunity and protection from infectious microorganisms, and also drive pathogenesis of chronic inflammatory diseases, such as asthma. ST2hi memory-type Th2 cells have been identified as a pathogenic subpopulation capable of directly inducing eosinophilic airway inflammation. These ST2hi pathogenic Th2 cells produce large amounts of IL-5 upon stimulation via their TCR, but not in response to IL-33. In contrast, IL-33 alone induces cytokine production in ST2+ group 2 innate lymphoid cells (ILC2). We investigated the molecular mechanism that controls the innate function of IL-33-induced cytokine production, and identified a MAPK phosphatase Dusp10, as a key negative regulator of IL-33–induced cytokine production in Th2 cells. We found that Dusp10 is expressed by ST2hi pathogenic Th2 cells but not by ILC2, and Dusp10 expression inhibits IL-33-induced cytokine production by preventing GATA3 activity through inhibition of p38 MAPK phosphorylation. Strikingly, deletion of Dusp10 rendered ST2hi Th2 cells able to directly respond to IL-33 exposure and produce IL-5. Thus, DUSP10 constrains IL-33–induced cytokine production in ST2hi pathogenic Th2 cells by controlling p38-mediated GATA3 function.

ORGANISM(S): Mus musculus

PROVIDER: GSE116842 | GEO | 2018/09/23

REPOSITORIES: GEO

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Project description:Background: Chronic rhinosinusitis with nasal polyposis (CRSwNP) in western countries is characterized by eosinophilia, IgE production and Th2 cytokine expression. Type 2 innate lymphoid cells (ILC2) from polyps produce IL-5 and IL-13 in response to IL-25 and IL-33 although the relevance of this axis to local mucosal T cell responses is unknown. Objective: To investigate the role of the IL-25/IL-33 axis in local mucosal T cell responses in CRSwNP. Methods: Polyp tissue and blood were obtained from patients undergoing nasal polypectomy. Control nasal biopsies and blood were obtained from healthy volunteers. Tissue was cultured in a short-term explant model. T cell surface phenotype/intracellular cytokines were assessed by flow cytometry. TCR VÎ² analysis was performed with the immunoSEQ assay. Microarrays were performed for gene expression analysis. Results: Using nasal polyp tissue, numerous IL-25 receptor (IL-17RB) positive polarized Th2 cells were identified which were absent in the healthy nasal mucosa and periphery. IL-17RB+CD4+ polyp Th2 cells co-expressed ST2 (IL-33 receptor) and responded to IL-25 and IL-33 with enhanced IL-5 and IL-13 production. Within IL-17RB+CD4+ T cells several identical TCR VÎ² CDR3 sequences were identified in different subjects suggesting clonal expansion driven by a common antigen. Abundant IL-17 producing T cells were observed in healthy nasal mucosal and polyp populations with Th17-related genes the most overexpressed compared to peripheral blood T cells. Conclusion: IL-25 and IL-33 may interact locally with IL-17RB+ST2+ polyp T cells to augment Th2 responses in CRSwNP. A local Th17 response may be the default signature in healthy nasal mucosal immune homeostasis. Three biological replicates. T-helper cells were isolated nasal polyps by explant culture from patients with chronic rhinosinusitis. Cells were then sorted based upon expression of IL17RB by flow cytometric sorting. Resting and activated IL-17RB+ve cells were compared with resting and activated IL-17RB-ve cells.

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DUSP10 constrains innate IL-33-mediated cytokine production in ST2hi memory-type pathogenic Th2 cells

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