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The phosphatidylinositol-transfer protein Nir3 promotes PI(4,5)P2 replenishment in response to TCR signaling during T cell development and survival

Wen Lu,Y. Helou,Krishna Shrinivas,J. Liou,Byron B. Au-Yeung,Arthur Weiss

Published 2022 in Nature Immunology

ABSTRACT

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. Weiss and colleagues identify a role for the endoplasmic reticulum-tethered PI transfer protein Nir3 in replenishing plasma membrane PIP2 levels in DN3-DP thymocytes, thereby increasing the sensitivity of developing thymocytes to weak TCR agonists.

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