Expression of CD25 in human lung mast cells and its regulation by IL-33.

Abstract

Expression of CD25, the IL-2 receptor alpha chain, on human mast cells is primarily associated with aberrant mast cells in clonal mast cell disorders. However, the regulation of CD25 expression in normal, mature tissue-resident mast cells remains poorly understood. IL-33 is a key modulator of immune responses, including in lung inflammatory conditions. Because mast cells are prominent IL-33 receptor-expressing cells, we investigated the effect of IL-33 on CD25 expression in purified human lung mast cells (HLMCs). Purified HLMCs were stimulated with IL-33 and the transcriptional responses measured by RNA sequencing. The expression of the IL-2 receptor subunits CD25 (IL2RA), CD122 (IL2RB), and CD132 (IL2RG) was quantified by real-time quantitative PCR and flow cytometry. IL2RA expression was further examined in publicly available single-cell RNA sequencing datasets, and in situ CD25 protein expression on HLMCs was assessed in human lung tissue by immunofluorescence staining. IL-33 robustly induced the expression of CD25 and CD132 in HLMCs without a corresponding upregulation of CD122, resulting in absent IL-2-mediated signaling despite enhanced IL-2 binding via CD25. Single-cell RNA sequencing data identified IL2RA⁺ mast cells as a distinct subpopulation with enriched IL-33 response signatures and upregulation of genes linked to immune signaling and inflammatory pathways. CD25-positive HLMCs were also detected in situ, displaying substantial heterogeneity in expression levels and spatial distribution. CD25 expression in HLMCs is upregulated by IL-33 and is dynamically regulated in human lung tissues.