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

Stem cell factor (SCF), also known as Kit ligand, is a pleiotropic cytokine that Q5 signals through the c-Kit receptor to regulate cellular development, survival, and proliferation. Although SCF is classically recognized for its essential role in hematopoiesis and mast cell biology, c-Kit is also expressed by innate lymphoid cell progenitors (ILCp) and subsets of mature innate lymphoid cells (ILCs), suggesting broader immunoregulatory functions. Group 2 innate lymphoid cells (ILC2s) are critical mediators of type 2 airway inflammation and serve as an important source of type 2 cytokines during allergic responses. We previously demonstrated increased expression of the pro-inflammatory SCF248 isoform in the lungs of mice with chronic allergic inflammation, while elevated soluble SCF levels have also been reported in patients with asthma. In the present study, we further observed that SCF248 is upregulated in the bone marrow during allergic inflammation, suggesting that SCF248 may contribute to both local and systemic regulation of allergic immune responses. 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.