The membrane lipid phosphatidylinositol-3,4,5-trisphosphate (PtdInsP3) regulates membrane receptor signalling in many cells, including immunoreceptor signalling. Here, we review recent data that have indicated essential roles for the soluble PtdInsP3 analogue inositol-1,3,4,5-tetrakisphosphate (InsP4) in T cell, B cell and neutrophil development and function. Decreased InsP4 production in leukocytes causes immunodeficiency in mice and might contribute to inflammatory vasculitis in Kawasaki disease in humans. InsP4-producing kinases could therefore provide attractive drug targets for inflammatory and infectious diseases.

Abstract

Pleckstrin homology (PH) domain–mediated protein recruitment to cellular membranes is of paramount importance for signal transduction. The recruitment of many PH domains is controlled through production and turnover of their membrane ligand, phosphatidylinositol 3,4,5-trisphosphate (PIP₃). We show that phosphorylation of the second messenger inositol 1,4,5-trisphosphate (IP₃) into inositol 1,3,4,5-tetrakisphosphate (IP₄) establishes another mode of PH domain regulation through a soluble ligand. At physiological concentrations, IP₄ promoted PH domain binding to PIP₃. In primary mouse CD4⁺CD8⁺ thymocytes, this was required for full activation of the protein tyrosine kinase Itk after T cell receptor engagement. Our data suggest that IP₄ establishes a feedback loop of phospholipase C–γ1 activation through Itk that is essential for T cell development.