Fibronectin Costimulation of CD40L Expression Integrates Innate and Adaptive Inflammatory Signals

Abstract

Abstract CD40 ligand (CD40L) is a well-known regulator of the adaptive immune response that induces and modulates the activation and differentiation of monocytes, dendritic cells, and lymphocytes. Less appreciated is its critical role in promoting the inflammatory response in CD40-expressing cells such as vascular endothelium. Expression of CD40L on TCR activated human CD4+ T cells is biphasic and upregulated by monocyte cell contact early and IL-2R signaling late. Here we demonstrate the existence of additional, distinct pathways that differentially regulate the expression of CD40L. We describe a novel link between vascular endothelial cell adhesion molecule 1 (VCAM-1), extracellular matrix (ECM) proteins, and CD40L expression on human CD4+T cells that constitutes an innate form of T cell costimulation modulated by the type and quantity of ECM protein present, with thrombospondin-1 inhibiting fibronectin-mediated costimulation of CD40L expression. Identification of this previously unrecognized β1 integrin pathway, which promotes CD40L expression on CD4+ T cells independently of monocytes and IL-2, provides new insights into our understanding of the potential role of CD40L in the establishment and progression of inflammatory disease.