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Low oxygen pressures exist in many solid tissues, including primary and secondary lymphoid organs. One key element in cellular adaptation to hypoxia is induced expression of hypoxia inducible factor (Hif) 1α. Here, we have examined the effect of Hif-1α, isolated from the myriad other effects of hypoxia, on T cell receptor (TCR) signaling in thymocytes. Because pVHL (von Hippel-Lindau protein) directs the proteolysis of Hif-1α under "normoxic" conditions, we achieved constitutive stabilization of Hif-1α through thymic deletion of Vhlh and reversed Hif-1α stabilization with double deletion of Vhlh and Hif-1α. We found that constitutive activity of Hif-1α resulted in diminished Ca²+ response upon TCR crosslinking despite equivalent activation of phospholipase Cγ1, normal intracellular Ca²+ stores, and normal entry of Ca²+ across the plasma membrane. Altered Ca²+ response was instead due to accelerated removal of Ca²+ from the cytoplasm into intracellular compartments, which occurred in association with Hif-1α-dependent overexpression of the calcium pump SERCA2 (sarcoplasmic/ endoplasmic reticulum calcium ATPase 2). These data suggest a unique mechanism for control of TCR signaling through Hif-1α, which may be operative at the physiologic oxygen tensions seen in solid lymphoid organs. [ABSTRACT FROM AUTHOR]