TCR Dependent Metabolic Programming Regulates Autocrine IL-4 Production Resulting in Self-Tuning of the CD8⁺ T Cell Activation Setpoint

The ability of T cells to sense and respond to environmental cues by altering their functional capabilities is critical for a safe and optimally protective immune response. One of the important properties that contributes to this goal is the activation set-point of the T cell. Here we report a new pathway through which TCR transgenic OT-I CD8⁺ T cells can self-tune their activation threshold. We find that in the presence of a strong TCR engagement event there is a shift in the metabolic programming of the cell where both glycolysis and oxidative phosphorylation are significantly increased. This diverges from the switch to a predominantly glycolytic profile that would be predicted following naïve T cell activation. Our data suggest this altered metabolic program results in the production of autocrine IL-4. Both metabolic pathways are required for this cytokine to be made. IL-4 signaling in the activated OT-I CD8⁺ T cell results in modulation of the sensitivity of the cell, establishing a higher activation setpoint that is maintained over time. Together these data demonstrate a novel mechanism for the regulation of IL-4 production in CD8⁺ T cells. Further, they reveal a new pathway for the self-tuning of peptide sensitivity. Finally, these studies uncover an unexpected role for oxidative phosphorylation in regulating differentiation in these cells.