The phosphatidylinositol-transfer protein Nir3 promotes PI(4,5)P(2) replenishment in response to TCR signaling during T cell development and survival

Hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP(2)) by phospholipase C-γ (PLCγ1) represents a critical step in T cell antigen receptor (TCR) signaling and subsequent thymocyte and T cell responses. PIP(2) replenishment following its depletion in the plasma membrane (PM) is dependent on delivery of its precursor phosphatidylinositol (PI) from the endoplasmic reticulum (ER) to the PM. We show that a PI transfer protein (PITP), Nir3 (Pitpnm2), promotes PIP(2) replenishment following TCR stimulation and is important for T cell development. In Nir3(–/–) T lineage cells, the PIP(2) replenishment following TCR stimulation is slower. Nir3 deficiency attenuates calcium mobilization in double-positive (DP) thymocytes in response to weak TCR stimulation. This impaired TCR signaling leads to attenuated thymocyte development at TCRβ selection and positive selection as well as diminished mature T cell fitness in Nir3(–/–) mice. This study highlights the importance of PIP(2) replenishment mediated by PITPs at ER-PM junctions during TCR signaling.