The actin cytoskeleton controls CD1d nanoclustering on the surface of APCs, fine-tuning iNKT activation. (A) Small basal nanoclusters of stimulating lipid-loaded CD1d molecules are present on the cell membrane of APCs. Barriers and/or obstacles by the actin cytoskeleton keep CD1d nanoclusters away from each other, limiting their aggregation state and regulating, in turn, iNKT cell activation, even under inflammatory conditions (iNKT cell autoreactivity). (B) Rearrangement of the actin cytoskeleton (achieved in our case by the use of CytoD treatment) increases the encountering rate between CD1d-1d nanoclusters, resulting in the formation of larger lipid-loaded CD1d nanoclusters and increased iNKT cell activation.