Hypoxia inducible factor 1α regulates T cell receptor signal transduction

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) 1 alpha. Here, we have examined the effect of Hif-1 alpha, 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-1 alpha under "normoxic" conditions, we achieved constitutive stabilization of Hif-1 alpha through thymic deletion of Vhlh and reversed Hif-1 alpha stabilization with double deletion of Vhlh and Hif-1 alpha. We found that constitutive activity of Hif-1 alpha resulted in diminished Ca2+ response upon TCR crosslinking despite equivalent activation of phospholipase C-gamma 1, 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-1 alpha-dependent overexpression of the calcium pump SERCA2 (sarcoplasmic/ encloplasmic reticulum calcium ATPase 2). These data suggest a unique mechanism for control of TCR signaling through Hif-1 alpha, which may be operative at the physiologic oxygen tensions seen in solid lymphoid organs.