Asthma is often induced by T helper type 2 (Th2) cells, which promote infiltration of eosinophils. However, due to the heterogeneity of asthma, there is also the presence of Th17 cells in the airway, inducing infiltration of neutrophils, and this type of asthma is often not sensitive to hormones [1]. Studies have shown that older patients have significantly increased rates of acute exacerbations of asthma compared to younger patients, and there are more neutrophils in the airways of older patients [2,3]. This issue has prompted an urgent need to improve research into the immune mechanisms of hormone resistance in asthma patients and develop such treatment options.

Bronchial epithelial cells (BECs) function not only as a structural barrier, but also as antigen-presenting cells (APCs). BECs play an important role in immune surveillance, and when stimulated by the external environment, these APCs present antigens to T cells, facilitating the antigen presentation process and subsequent T cell differentiation [[4], [5], [6]]. We found that BECs can directly regulate the differentiation of CD4+ T cells in vitro [7]. However, considering the high incidence of acute exacerbations and hormone resistance in elderly asthma, further studies are needed to better understand the potential role of BECs as APCs in asthma and to determine whether there are differences in the phenotype of CD4+ T cell differentiation induced by BECs at different ages.

Previous studies have shown that allergen-stimulated BECs undergo abnormal DNA methylation, which may be regulated by epigenetic mechanisms [8]. Additionally, cellular senescence alters the DNA methylation status of cells [9]. However, the effect of BECs on DNA methylation at different ages remains unknown. Methyl-CpG binding domain (MBD) proteins play a “reader” and regulatory role in the DNA methylation process, with MBD2 being a member of this family [10,11]. MBD2 has been implicated in the pathogenesis of experimental colitis, rheumatoid arthritis, and other immune diseases [[12], [13], [14]]. Our previous studies have demonstrated that MBD2 is highly expressed in BECs from asthma models and positively regulates Th17 cell differentiation [8,15]. However, it remains unclear whether MBD2 can regulate CD4+ T cell differentiation in BECs at different ages.

Inducible T cell costimulatory (ICOS) ligands (ICOSL), a member of the B7 family of ligands, exist in two forms: membrane-type and soluble-type (sICOSL). The membrane-type generally exists in a structural form, while the soluble-type is predominantly functional [16,17]. ICOSL is expressed by a variety of cell types, including B cells, dendritic cells, vascular endothelial cells, and epithelial cells [18,19]. ICOSL is a ligand corresponding to ICOS, a member of the CD28 receptor family. Studies have demonstrated that ICOS-ICOSL signaling is essential for Th cell differentiation. When ICOSL is functionally altered, it can lead to immune deficiency and even induce autoimmune diseases [16,20,21]. Notably, allergen stimulation of dendritic cells has been shown to induce ICOSL expression and enhance Th2 differentiation [22]. However, it remains unclear whether allergen-induced BECs at different ages can trigger the expression of sICOSL.

In this study, recognizing that sICOSL is the functional form of ICOSL, we sought to determine the role of MBD2 and sICOSL in BECs-induced asthma models across different age groups. In our research, BECs were co-cultured with CD4+ T cells, revealing that BECs from young mice promoted Th2 cell differentiation, while BECs from old mice promoted Th17 cell differentiation. Notably, MBD2 expression was higher on BECs of older mice compared to those of younger mice, and sICOSL levels in BECs of older mice were lower than in BECs of younger mice. Mechanistically, silencing MBD2 promoted the expression of sICOSL and inhibited Th17 cell differentiation. As anticipated, the incorporation of anti-sICOSL antibodies notably enhanced Th17 cell differentiation and concurrently suppressed Th2 cell differentiation. Conversely, the supplementation of exogenous sICOSL impaired Th17 cell differentiation and facilitated Th2 cell differentiation. Collectively, these findings suggest that BECs from older mice regulate Th17 cell differentiation via the MBD2-sICOSL axis. These insights provide novel understanding into the pathogenesis of Th17-activated asthma in elderly patients.