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Differential and cooperative effects of IL-25 and IL-33 on T helper cells contribute to cryptococcal virulence and brain infection

ABSTRACT: Cryptococcal disease pathogenesis is associated with the induction of type 2 immune response which is largely mediated by adaptive T helper cells. Recently, epithelial cell-derived IL-33 and IL-25 are recognized as key mediators in driving pathogenic type 2 inflammation during C. neoformans infection. Although IL-25 and IL-33 exhibit a combinatorial and closely related function, the differential effect of these cytokines in the regulation of host immune response against C. neoformans infection is still elusive. We observed a predominantly increase of IL-25/IL-33 responsive Th cells within the lung after infection, especially at the chronic infection phase. The ex vivo stimulation of cryptococcal-specific Th cells demonstrated combinatorial effect of IL-25 and IL-33 in promoting the production of type 2 cytokines. A comparative transcriptomic analysis revealed coordinatel effects of these cytokines in promoting activation, survival, and homeostasis of adaptive Th cells during C. neoformans infection. The expression of type 2 cytokines and chemokine was absent in Th cells of Il17rb-/- mice, indicating the requirement of IL-25-mediated Th2-type immune responses during C. neoformans infection. Further analysis of the degree of virulence indicated a positive correlation between the frequency of IL-17RB/ST2-expressing Th cells and cryptococcal brain dissemination in vivo.

ORGANISM(S): Mus musculus

PROVIDER: GSE229703 | GEO | 2023/06/18

REPOSITORIES: GEO

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Differential and cooperative effects of IL-25 and IL-33 on T helper cells contribute to cryptococcal virulence and brain infection

Project description:Differential and cooperative effects of IL-25 and IL-33 on T helper cells contribute to cryptococcal virulence and brain infection

| PRJNA955657 | ENA

Transcriptome profiling of T-helper cells from normal nassal mucosa and matched peripheral blood

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 Vβ 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 Vβ 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.

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