Resolving mechanisms of T cell activation at the single molecule level

T cells mount an immune response to foreign pathogens by searching the surface of antigen presenting cells for cognate antigens, and their specific recognition by the T cell receptor (TCR). First engagement between these cells occurs via dynamic T cell protrusions, e.g. microvilli, before forming a tight immune synapse. We used single molecule localization microscopy (SMLM) in live cells to resolve TCR-dependent signaling at tight cell contacts. We show that early contacts are sufficient for robust TCR triggering and its rapid signal amplification. We further show dynamic nanoscale molecular patterning of the TCR and related signaling and structural proteins at the tight contacts that facilitates T cell activation. Thus, early and tight T cell contacts function as both sensing and decision-making entities in T cell activation.