THE INOSITOL 1,4,5-TRISPHOSPHATE RECEPTOR IS ESSENTIAL FOR T-CELL RECEPTOR SIGNALING

Antigen-specific activation of T lymphocytes, via stimulation of the T -cell antigen receptor (TCR) complex, is marked by a rapid and sustain ed increase in the concentration of cytoplasmic free Ca2+ ([Ca2+](i)). It has been suggested that the second messenger inositol 1,4,5-trisph osphate (IP3) produced after TCR stimulation binds to the IP3 receptor (IP(3)R), an intracellular Ca2+-release channel, and triggers the inc rease in [Ca2+](i) that activates transcription of the gene for T-cell growth factor interleukin 2 (IL-2). However, the role of the IP(3)R i n T-cell signaling and possibly in plasma membrane Ca2+ influx in T ce lls remains unproven. Stable transfection of T cells (Jurkat) with ant isense type 1 IP(3)R cDNA prevented type 1 IP(3)R expression, providin g a tool for dissecting the role of IP3 signaling during T-cell activa tion. T cells lacking type 1 IP(3)R failed to increase [Ca2+](i) or pr oduce IL-2 after TCR stimulation, Moreover, depletion of intracellular Ca2+ stores without TCR activation stimulated Ca2+ influx in cells la cking the type 1 IP(3)R. These results establish that the type 1 IP(3) R is required for intracellular Ca2+ release that triggers antigen-spe cific T-cell proliferation but not for plasma membrane Ca2+ influx.