@article{0282fbd6ce224f96af70f53dfa38bd4f,
title = "The phosphatidylinositol-transfer protein Nir3 promotes PI(4,5)P2 replenishment in response to TCR signaling during T cell development and survival",
abstract = "Hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by phospholipase C-γ (PLCγ1) represents a critical step in T cell antigen receptor (TCR) signaling and subsequent thymocyte and T cell responses. PIP2 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 PIP2 replenishment following TCR stimulation and is important for T cell development. In Nir3–/– T lineage cells, the PIP2 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 PIP2 replenishment mediated by PITPs at ER-PM junctions during TCR signaling.",
author = "Wen Lu and Helou, {Ynes A.} and Krishna Shrinivas and Jen Liou and Au-Yeung, {Byron B.} and Arthur Weiss",
note = "Funding Information: We thank J. Zikherman for her constructive suggestions regarding this paper. We thank M. Krangel and A. Naik for their valuable consultations of methodology for TCR repertoire analysis. We thank A. Roque for animal husbandry, J. Mueller and W. Lo for irradiation of mice, UCSF Parnassus Flow Cytometry Core for maintaining FACSArias instruments and services, the Gladstone transgenic core facility for generating Nir3 mice, W. Lo for testing gRNA in EL4 cells and NIH Tetramer Core Facility for providing the H-2Kb OVA tetramers. This work was supported by in part by the Howard Hughes Medical Institute, the NIH (grants NIAID R37 AI114575 (A.W.), NIGMS R01 GM 144479 (J.L.) and NIAMS K01 AR065481 (B.B.A.)) and DRC Center Grant P30 DK063720 (UCSF Parnassus Flow Cytometry Core, UCSF Diabetes Center). –/– Funding Information: We thank J. Zikherman for her constructive suggestions regarding this paper. We thank M. Krangel and A. Naik for their valuable consultations of methodology for TCR repertoire analysis. We thank A. Roque for animal husbandry, J. Mueller and W. Lo for irradiation of mice, UCSF Parnassus Flow Cytometry Core for maintaining FACSArias instruments and services, the Gladstone transgenic core facility for generating Nir3–/–mice, W. Lo for testing gRNA in EL4 cells and NIH Tetramer Core Facility for providing the H-2Kb OVA tetramers. This work was supported by in part by the Howard Hughes Medical Institute, the NIH (grants NIAID R37 AI114575 (A.W.), NIGMS R01 GM 144479 (J.L.) and NIAMS K01 AR065481 (B.B.A.)) and DRC Center Grant P30 DK063720 (UCSF Parnassus Flow Cytometry Core, UCSF Diabetes Center). Publisher Copyright: {\textcopyright} 2022, The Author(s).",
year = "2023",
month = jan,
doi = "10.1038/s41590-022-01372-2",
language = "English (US)",
volume = "24",
pages = "136--147",
journal = "Nature immunology",
issn = "1529-2908",
publisher = "Nature Publishing Group",
number = "1",
}