Targeting CD48 Ameliorates ILC2-mediated Airway Hyperreactivity by Disrupting the PKCβ Pathway.

Abstract

CD48 is a cell surface protein belonging to the signaling lymphocyte activation molecule family and is known to regulate immune cell function. Although asthma has traditionally been associated with adaptive immune responses, recent evidence highlights a central role for group 2 innate lymphoid cells (ILC2s) in orchestrating type 2 inflammation, independent of adaptive immunity. Here, we investigated the immunomodulatory function of CD48 on ILC2s and its contribution to the development of airway inflammation and airway hyperreactivity (AHR). Using an ILC2 dependent induced murine model of asthma, we employed both CD48 knockout mice and blocking antibodies to dissect the role of CD48 in vivo. We found that CD48 is expressed on lung-resident ILC2s, and its absence significantly impairs ILC2 activation, reduces eosinophilic infiltration, and alleviates AHR. Adoptive transfer experiments further confirmed that these effects are ILC2-intrinsic. Transcriptomic profiling of CD48-deficient ILC2s revealed downregulation of key effector genes and enrichment of pathways involving PI3K and protein kinase C beta (PKCβ). Pharmacologic modulation of PKCβ altered ILC2 cytokine production in a CD48-dependent manner, establishing a mechanistic link between CD48 signaling and ILC2 function. Moreover, human ILC2s isolated from peripheral blood and cultured under activating conditions upregulated CD48, and blockade of CD48 suppressed ILC2s cytokine production. In a humanized mouse model, CD48 inhibition likewise reduced airway inflammation, mirroring findings in murine systems. These results identify CD48 as a critical regulator of ILC2-driven AHR and suggest that targeting CD48 or its downstream signaling pathways may offer novel therapeutic opportunities for the treatment of asthma.