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T-Cell Activation under Hypoxic Conditions Enhances IFN- Secretion

¹ Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland; ² Division of Pulmonary and Critical Care Medicine, University of Rochester Medical Center, Rochester, New York; ³ Division of Rheumatology, Johns Hopkins University, Baltimore, Maryland; and ⁴ Vascular Program, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, Maryland

Correspondence and requests for reprints should be addressed to Steve N. Georas, M.D., University of Rochester Medical Center, 601 Elmwood Avenue, Box 692, Rochester, NY 14642-8692. E-mail: steve_georas{at}urmc.rochester.edu

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% O₂) and hypoxic (1% O₂) conditions. Here we report that stimulation under hypoxic conditions augments the secretion of effector CD4⁺ T-cell cytokines, especially IFN-. The enhancing effects of hypoxia on IFN- 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-1. Using T cells from IFN- receptor–deficient mice and promoter reporter studies in transiently transfected Jurkat T cells, we found that the enhancing effects of hypoxia on IFN- expression were not due to effects on IFN- 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- secretion and other cytokines. We conclude that hypoxia is a previously underappreciated modulator of effector cytokine secretion in CD4⁺ T cells.

Key Words: hypoxia • gene regulation • CD4⁺ T cells • effector cytokine • IFN-

CLINICAL RELEVANCE T lymphocytes will be exposed to low ambient oxygen concentrations during recirculation through secondary lymphoid organs and in inflamed tissues. Relatively little is known about the effects of hypoxia on T cells. Our finding, that IFN- secretion is particularly enhanced under hypoxic conditions, suggests that the oxygen-rich pulmonary environment may not be as effective as other tissues in supporting maximal IFN- secretion in a T cell–autonomous manner.