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 sustained increase in the concentration of cytoplasmic free Ca²⁺ ([Ca²⁺](i)). It has been suggested that the second messenger inositol 1,4,5-trisphosphate (IP₃) produced after TCR stimulation binds to the IP₃ receptor (IP₃R), an intracellular Ca²⁺-release channel, and triggers the increase in [Ca²⁺](i) that activates transcription of the gene for T-cell growth factor interleukin 2 (IL-2). However, the role of the IP₃R in T-cell signaling and possibly in plasma membrane Ca²⁺ influx in T cells remains unproven. Stable transfection of T cells (Jurkat) with antisense type 1 IP₃R cDNA prevented type 1 IP₃R expression, providing a tool for dissecting the role of IP₃ signaling during T-cell activation. T cells lacking type 1 IP₃R failed to increase [Ca²⁺](i) or produce IL-2 after TCR stimulation. Moreover, depletion of intracellular Ca²⁺ stores without TCR activation stimulated Ca²⁺ influx in cells lacking the type 1 IP₃R. These results establish that the type 1 IP₃R is required for intracellular Ca²⁺ release that triggers antigen-specific T-cell proliferation but not for plasma membrane Ca²⁺ influx.