T cell responses to antigen: hasty proposals resolved through long engagements

T cells discriminate between peptide-MHC complexes on the surfaces of antigen presenting cells to enact appropriate downstream responses. Great progress has been made over the last 15 years in understanding varied aspects of T cell activation on short timescales (minutes), yet the mechanics and significance of long term T cell receptor signaling (hours or days) remain unclear. Furthermore, there remain some controversies regarding the correlation of the biophysical parameters of ligand–receptor interactions with the scaling of downstream effector functions.Here we review recent studies that emphasize the importance of long-term engagement of antigens to fine-tuning the activation of T cells over the duration of the complete immune response. We discuss how T cells dynamically regulate T cell receptor signaling via antigen crosstalk, competition and consumption to accurately counter antigenic challenges.

► Digital T cell activation exhibits a saturated dynamic range on short timescales. ► Persistent antigen engagement fine-tunes response through time integration of signals. ► Antigen-mediated cross-talk and feedbacks extend the dynamic range of T cell outputs. ► Competition for antigen limits TCR signal duration and normalizes for population size. ► Antigen consumption (trogocytosis) regulates T cell signaling over long timescales.