Stem cell factor 248 shapes ILC2 transcriptional programs and promotes mucosal inflammation in allergic asthma

To define the role of SCF/c-Kit signaling in ILC2 biology, we first performed transcriptional profiling of SCF-deficient ILC2s, which revealed reduced expression of genes associated with cytokine signaling, activation, and effector function, including Il4, Stat5b, and PI3K-AKT pathway components, consistent with impaired inflammatory responsiveness. Mechanistically, pro-inflammatory and type 2 cytokines induced SCF248 expression in mesenchymal cells in vitro.

To define its functional impact, ILC progenitors were cultured on OP9-DL1 stromal cells with upregulated SCF248 expression, which increased expression of ILC2-associated markers and the maturation program, supporting a role for SCF248 in enhancing ILC2 maturation and activation. In vivo validation using tamoxifen-inducible whole-body SCF-deficient mice (SCFfl/fl; UBC-CreERT2) in an Alternaria alternata model of allergic airway inflammation demonstrated that SCF deficiency reduced SCF248 expression, attenuated type 2 cytokine production, diminished lung inflammation, and decreased circulating and pulmonary ILC2 populations.

Similarly, SCF248 blockade reduced allergic inflammation and altered bone marrow ILC compartments. Together, these findings identify SCF248 as a regulator of ILC2 maturation and activation, amplifying mucosal type 2 inflammation during allergic airway disease.