T-cell activation under hypoxic conditions enhances IFN-gamma secretion.
Secondary lymphoid organs and peripheral tissues are characterized by hypoxic microenvironments, both in the steady state and during inflammation. Although hypoxia regulates T-cell metabolism and survival, very little is known about whether or how hypoxia influences T-cell activation. We stimulated mouse CD4(+) T cells in vitro with antibodies directed against the T-cell receptor (CD3) and CD28 under normoxic (20% O(2)) and hypoxic (1% O(2)) conditions. Here we report that stimulation under hypoxic conditions augments the secretion of effector CD4(+) T-cell cytokines, especially IFN-gamma. The enhancing effects of hypoxia on IFN-gamma secretion were independent of mouse strain, and were also unaffected using CD4(+) T cells from mice lacking one copy of the gene encoding hypoxia-inducible factor-1alpha. Using T cells from IFN-gamma receptor-deficient mice and promoter reporter studies in transiently transfected Jurkat T cells, we found that the enhancing effects of hypoxia on IFN-gamma expression were not due to effects on IFN-gamma consumption or proximal promoter activity. In contrast, deletion of the transcription factor, nuclear erythroid 2 p45-related factor 2 attenuated the enhancing effect of hypoxia on IFN-gamma secretion and other cytokines. We conclude that hypoxia is a previously underappreciated modulator of effector cytokine secretion in CD4(+) T cells.
University of Rochester Medical Center, 601 Elmwood Avenue, Rochester, NY 14642-8692, USA.
Jessica
J
Roman
Tirumalai
T
Rangasamy
Jia
J
Guo
Siva
S
Sugunan
Nida
N
Meednu
Gopinath
G
Packirisamy
Larissa A
LA
Shimoda
Amit
A
Golding
Gregg
G
Semenza
Steve N
SN
Georas
D000818:Animals; D017252:CD3 Complex / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D000860:Hypoxia; D007371:Interferon-gamma / Q000378:metabolism*; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010100:Oxygen / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology*
D017252:CD3 Complex; D007371:Interferon-gamma; D010100:Oxygen