Regulated cytoskeletal control of ICAM-1 mobility on the dendritic cell plasma membrane enhances T cell activation (P1205)

Abstract

Abstract T cell activation involves actin-dependent assembly and centripetal movement of signaling microclusters at the Immune Synapse (IS). Model stimulatory surfaces that limit microcluster dynamics enhance TCR signaling, but the possibility that antigen presenting cells can modulate T cell signaling by regulating ligand distribution is largely unexplored. Dendritic cells (DCs) form a multi-focal IS rather than the concentric pattern seen with freely mobile ligands, suggesting that DCs can control receptor-ligand localization. We have measured the lateral mobility of T cell ligands on the DC membrane, and find that ICAM-1, the key ligand for the integrin LFA-1, is selectively constrained via interactions with the actin cytoskeleton. ICAM-1 mobility decreases further upon LPS-induced DC maturation, concomitant with upregulation moesin and α-actinin 1, two actin-binding proteins that bind the cytoplasmic tail of ICAM-1. ICAM-1 co-localizes with moesin at punctate sites on the DC surface. Mutation of the ICAM-1 cytoplasmic tail or suppression of moesin and/or α-actinin liberates ICAM-1 lateral mobility. Importantly, liberating ICAM-1 from cytoskeletal constraints decreases the ability of DCs to induce the proliferation of naïve CD4 T cells. Taken together, our data show that the DC actin cytoskeleton actively controls ligand mobility and thus enhances T cell activation, and raise the possibility that DCs modulate T cell signaling by actively regulating molecular dynamics at the IS.