Timed Regulation of 3BP2 Induction Is Critical for Sustaining CD8⁺ T Cell Expansion and Differentiation

Successful anti-viral response requires the sustained activation and expansion of CD8⁺ T cells for periods that far exceed the time limit of physical T cell interaction with antigen-presenting cells (APCs). The expanding CD8⁺ T cell pool generates the effector and memory cell populations that provide viral clearance and long-term immunity, respectively. Here, we demonstrate that 3BP2 is recruited in cytoplasmic microclusters and nucleates a signaling complex that facilitates MHC:peptide-independent activation of signaling pathways downstream of the TCR. We show that induction of the adaptor molecule 3BP2 is a sensor of TCR signal strength and is critical for sustaining CD8⁺ T cell proliferation and regulating effector and memory differentiation. Dimitriou et al. show that the adaptor protein 3BP2 lowers the threshold of T cell activation and that the induction of the 3BP2 signaling module at later time points may serve to recapitulate and prolong the biochemical signals emanating from the TCR required for sustained MHC:peptide-independent T cell proliferation.