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

Abstract

The majority of in vitro studies involving lymphocytes is performed in AtmO(2), and the PhysO(2) that T cells encounter are variable but commonly much lower. Previous studies showed changed kinetics and delayed proliferation of human T cells at PhysO(2). Here, we show that CD3/CD28-dependent T cell activation induces faster cell cycling at AtmO(2) than at PhysO(2) (here taken to be 2%). Concomitantly with HIF-1alpha expression, we observed a switch in the T cell respiratory pathway toward glycolysis at PhysO(2). Thus, modulating available glucose levels showed that at PhysO(2), T cells rely more on glycolysis, associated with a higher phosphorylation of Akt(ser473). Although no difference in spontaneous apoptosis of resting cells was detected, it was increased significantly at PhysO(2) 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.

Overexpression of hypoxia‐inducible factor 1 alpha impacts FoxP3 levels in mycosis fungoides—Cutaneous T‐cell lymphoma: Clinical implications

“…26,32 In addition, there is evidence that HIF-1a can negatively regulate the T-cell response. 33 Interestingly, two recent reports showed that HIF-1a could modulate the Th17/ Treg balance, promoting IL-17 transcription and FoxP3 degradation. 24,27 However, both the role of HIF-1a in FoxP3 regulation in CD4 1 T cells in human skin and its possible contribution to skin pathologies remain unknown.…”

“…27,41 The expression of HIF-1a in activated T cells has important implications in the regulation of the T cell response. 27,33 It was recently demonstrated in experimental models that HIF-1a can regulate FoxP3 degradation under both hypoxic and normoxic conditions. 23,24,27,42 Our results showed that the overall expression of FoxP3 was decreased in early stage MF patients and declined further with disease progression, which is consistent with previous reports.…”

Glut1-mediated glucose transport regulates HIV infection

“…Thus, although lymphocytes encounter fluctuations in O 2 levels in vivo, the physiological range of O 2 levels to which they are exposed is at least two to six times lower than the 20% O 2 levels maintained in standard incubators. Culturing at atmospheric O 2 levels has been shown to result in altered cell proliferation rates and other skewed T-cell responses (16,(19)(20)(21)(22)(23). Thus, because the goal of in vitro studies is generally to reveal information of in vivo significance, our studies here focus on findings with peripheral blood T cells cultured at physiological O 2 levels.…”

L’hypoxie tumorale

“…D'autres travaux montrent, au contraire, que lorsque les cellules T sont activées, l'hypoxie favorise leur survie en prévenant la mort dite AICD (activation-induced cell death) [34]. L'activation de l'apoptose ou des voies de survie en hypoxie semble donc influencée par l'état d'activation des cellules T. L'hypoxie réduit également la prolifération des cellules T activées [35] et la production de cytokines (IL-2, IFN) [36], mais les fonctions lytiques des cellules T CD8 + seraient augmentées [36]. Les cellules T semblent donc pouvoir être fonctionnelles dans un environnement hypoxique.…”