IL-25/IL-33-responsive TH2 cells characterize nasal polyps with a default TH17 signature in nasal mucosa

Background: Chronic rhinosinusitis with nasal polyposis (CRSwNP) in Western countries is characterized by eosinophilia, IgE production, and T(H)2 cytokine expression. Type 2 innate lymphoid cells 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: We sought to investigate the role of the IL-25/IL-33 axis in local mucosal T-cell responses in patients with CRSwNP. Methods: Polyp tissue and blood were obtained from patients undergoing nasal polypectomy. Control nasal biopsy specimens 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 means of flow cytometry. T-cell receptor variable beta-chain analysis was performed with the immunoSEQ assay. Microarrays were performed for gene expression analysis. Results: IL-25 receptor (IL-17RB)-expressing T(H)2 effector cells were identified in nasal polyp tissue but not the healthy nasal mucosa or periphery. IL-17RB(+) CD4(+) polyp-derived T(H)2 cells coexpressed 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 T-cell receptor variable beta-chain complementarity-determining region 3 sequences were identified in different subjects, suggesting clonal expansion driven by a common antigen. Abundant IL-17-producing T cells were observed in both healthy nasal mucosal and polyp populations,with T(H)17-related genes the most overexpressed compared with peripheral blood T cells. Conclusion: IL-25 and IL-33 can interact locally with IL-17RB(+) ST2(+) polyp T cells to augment T(H)2 responses in patients with CRSwNP. A local T(H)17 response might be important in healthy nasal mucosal immune homeostasis.