IL-2 mediates human bystander CD8+ T-cell responses to innate immune signals

In response to an infection, the host T cell compartment develops immunological memory to ensure rapid responses upon re-infection with the same pathogen. However, these memory responses can also modulate immune reactions to unrelated pathogens through bystander activation. Herein, T cells are activated in an antigen-independent manner, often triggered by innate cytokines or Toll-like receptor ligands. To uncover new strategies for modulating immune responses, it is essential to deepen our understanding of this alternative mechanism of T cell activation, particularly in humans. Therefore, we studied the response of human CD8+ T cells to innate bystander stimuli in vitro. Thereby, we measured the induction of activation markers and proliferation using flow cytometry, and depleted or blocked several potential modulatory components to identify mediators of bystander CD8+ T-cell responses. Our study demonstrates that CD8+ T cells can be activated as bystander cells in response to innate stimuli present during a viral infection, including IL-15, IFN-α, and TLR7/8 and 9 agonists (R848 and CpG). Depletion experiments demonstrated that these bystander responses are dependent on monocytes and CD4+ T cells. In addition, we revealed that the bystander responses to the innate stimuli are highly reliant on IL-2 signaling. Altogether, our study underscores the pivotal role of IL-2 in mediating bystander responses of CD8+ T cells to innate stimuli, revealing a novel mechanism of immune response modulation during viral infections.