Deciphering the role of the nanoscale clustering of activating and costimulatory antibodies on T cell activation

In a joint experimental and a modeling effort, we explored the regulation of T cell activation and cytotoxicity by the nanoscale clustering and surface density of activating and costimulatory antibodies. Specifically, we simulated T cells on nanolithographically patterned arrays of clusters of these antibodies, systematically varying the cluster size from intermediate to large and overall antibody density. We found that T-cell activation correlated more with global antibody density than with cluster size, such that at low density arrays were inefficient in activation, while high density arrays saturated the signal. However, when T-cells were exposed to patterns of low global densities but small, very dense clusters, full activation of T cells was achieved. These results could be rationalized using the membrane-fluctuation-model that integrates the cooperative effects between bonds with mechanical feedback from the cell activation. This insight into the spatial organization of activating ligands provides an important understanding of the mechanism of T cell activation and allows for the design of more effective T cell activation platforms for immunotherapy.