Cell adaptation to hypoxia is partially accomplished by hypoxia-inducible transcription factor-1 (HIF-1). Here we report the hypoxia-independent upregulation of HIF-1a subunit in antigen receptor-activated T cells. This is explained by selective upregulation of alternatively spliced mRNA isoform I.1 which encodes the HIF-1a protein without first twelve N-terminal amino acids. We show, that both short (I.1) and long (I.2) HIF-1a isoforms display similar DNA-binding and transcriptional activities. Major differences were observed between these two HIF-1a isoforms in their expression patterns with respect to the resting and activated T lymphocytes under hypoxic and normoxic conditions. The TCR-triggered activation of normal ex vivo T cells and differentiated T cells results in upregulation of expression of I.1 isoform of HIF-1a mRNA without an effect on constitutive I.2 HIF-1a mRNA expression. The accumulation of I.1 HIF-1a mRNA isoform in T lymphocytes is also demonstrated during cytokine mediated inflammation in vivo suggesting a physiological role of short HIF-1a isoform in activated lymphocytes. The TCR-triggered, protein kinase C and Ca2+/calcineurin-mediated HIF-1a I.1 mRNA induction is protein synthesis-independent, suggesting that the HIF-1a I.1 gene is expressed as an immediate-early response gene. Therefore these data predict a different physiological role of short and long isoforms of HIF-1a in resting and activated cells.