Induction of HIF‐1α and the glycolytic pathway alters apoptotic and differentiation profiles of activated human T cells

The majority of in vitro studies involving lymphocytes is performed in AtmO2, and the PhysO2 that T cells encounter are variable but commonly much lower. Previous studies showed changed kinetics and delayed proliferation of human T cells at PhysO2. Here, we show that CD3/CD28‐dependent T cell activation induces faster cell cycling at AtmO2 than at PhysO2 (here taken to be 2%). Concomitantly with HIF‐1α expression, we observed a switch in the T cell respiratory pathway toward glycolysis at PhysO2. Thus, modulating available glucose levels showed that at PhysO2, T cells rely more on glycolysis, associated with a higher phosphorylation of Aktser473. Although no difference in spontaneous apoptosis of resting cells was detected, it was increased significantly at PhysO2 after T cell activation and was different within the different T cell subsets. This may explain at least partly the differently altered proliferation and subset distribution observed in CD4+ and CD8+ T cells as a result of differences in naïve and memory subset distribution. Together, these findings suggest that T cell activation thresholds, subsequent proliferative capacity, and susceptibility to apoptosis, hitherto studied in air and thought to be crucial for monitoring immune responsiveness, may require re‐assessment.