title: Pathophysiological hypoxia affects the redox state and IL-2 signalling of human CD4+ T cells and concomitantly impairs survival and proliferation.
abstract: Inflamed areas are characterized by infiltration of immune cells, local hypoxia and alterations of cellular redox states. We investigated the impact of hypoxia on survival, proliferation, cytokine secretion, intracellular energy and redox state of human CD4(+) T cells. We found that pathophysiological hypoxia (<2% O2 ) significantly decreased CD4(+) T-cell survival after mitogenic stimulation. This effect was not due to an increased caspase-3/7-mediated apoptosis or adenosine-5'-triphosphate (ATP) consumption/depletion. However, the ability of stimulated T cells to proliferate was reduced under hypoxic conditions, despite increased expression of CD25. Pathophysiological hypoxia was also found to modify intracellular ROS (iROS) levels in stimulated T cells over time as compared with levels found in normoxia. Physiological hypoxia (5% O2 ) did not decrease CD4(+) T-cell survival and proliferation or modify iROS levels as compared with normoxia. We conclude that pathophysiological hypoxia affects T-cell proliferation and viability via disturbed IL-2R signalling downstream of STAT5a phosphorylation, but not as a result of impaired cellular energy homeostasis. We suggest iROS links early events in T-cell stimulation to the inhibition of the lymphoproliferative response under pathophysiological hypoxic conditions. The level of iROS may therefore act as a mediator of immune functions leading to down-regulation of long-term T-cell activity in inflamed tissues.
authors.affiliation: Department of Rheumatology and Clinical Immunology, Charité University Hospital, Berlin, Germany. gaber@drfz.de
authors.forename: Timo
authors.initials: T
authors.lastname: Gaber
authors.forename: Cam Loan
authors.initials: CL
authors.lastname: Tran
authors.forename: Saskia
authors.initials: S
authors.lastname: Schellmann
authors.forename: Martin
authors.initials: M
authors.lastname: Hahne
authors.forename: Cindy
authors.initials: C
authors.lastname: Strehl
authors.forename: Paula
authors.initials: P
authors.lastname: Hoff
authors.forename: Andreas
authors.initials: A
authors.lastname: Radbruch
authors.forename: Gerd-Rüdiger
authors.initials: GR
authors.lastname: Burmester
authors.forename: Frank
authors.initials: F
authors.lastname: Buttgereit
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D015687:Cell Hypoxia / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D017382:Reactive Oxygen Species; D050799:STAT5 Transcription Factor