Pathogen-Specific Inflammatory Milieux Tune the Antigen Sensitivity of CD8⁺ T Cells by Enhancing T Cell Receptor Signaling

CD8⁺ T cells confer host protection through T-cell-receptor (TCR)-mediated recognition of foreign antigens presented by infected cells. Thus, generation of CD8⁺ T cell populations with high antigen sensitivity is critical for efficient pathogen clearance. Besides selection of high-affinity TCRs, the molecular mechanisms regulating the antigen sensitivity of CD8⁺ T cells remain poorly defined. Herein, we have demonstrated that the antigen sensitivity of effector and memory CD8⁺ T cells is dynamically regulated and can be tuned by pathogen-induced inflammatory milieux independently of the selection of cells with higher TCR affinity. Mechanistically, we have demonstrated that the signal-transduction capacity of key TCR proximal molecules is enhanced by inflammatory cytokines, which reduced the antigen density required to trigger antimicrobial functions. Dynamic tuning of CD8⁺ T cell antigen sensitivity by inflammatory cytokines most likely optimizes immunity to specific pathogens while minimizing the risk of immunopathology at steady state.