ICOSL: more than a trigger of ICOS function.

Inducible T-cell costimulator (ICOS) and its ligand ICOSL are members of the CD28 and B7 receptor families that play central roles in immune regulation. While the role of ICOS in T-cell activation and differentiation has been widely studied, increasing evidence indicates that ICOSL, which is broadly expressed across both immune and nonimmune cell types, also functions as a signaling receptor. This review focuses on ICOSL-mediated reverse signaling and its ability to modulate the behavior of ICOSL-expressing immune and stromal cells. In vitro, ICOSL activation induces cell type-specific responses, most notably regulating cell migration. In vivo, ICOSL signaling influences key processes such as tumor growth, bone remodeling, wound healing, liver regeneration, and sepsis. Taken together, these findings expand the conventional view of ICOSL as a passive ligand and suggest that ICOSL is a versatile immune modulator with therapeutic relevance in cancer, inflammatory, and fibrotic diseases.