Spatiotemporal co-regulation of IL2 and TCR receptors reveals early antigen-driven synaptic synergy in human CD8+ T cells

Abstract Interleukin 2 (IL2) promotes T cell proliferation and differentiation, making it a central target in immunotherapies. Following antigen recognition, IL2 receptor (IL2R) signaling polarizes towards the immunological synapse (IS). However, how IL2 function is integrated during earlier antigen-dependent T cell synapses remains unknown. Here, we employ a supported-lipid bilayer system and TIRF microscopy to monitor the IL2R subunits and their spatiotemporal organization relative to T cell receptor (TCR) at the IS of CD8 + T cells. We show that TCR and IL2 signaling overlap in space and time and synergize when simultaneously triggered. Using Immuno-STATs, a class of immunotherapeutics in clinical testing that co-deliver IL2 and peptide major histocompatibility complex (pMHC), we demonstrate synergistic TCR and IL2R signaling that drives efficient expansion of antigen-specific CD8 + T cells. Together, these findings establish the IS as a platform for coordinated cytokine and antigen receptor signaling, providing a mechanistic framework for more selective antigen-specific immunotherapies.