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

• Type of Material: Article
• Authors: Wen Lu, University of California San Francisco; Ynes A Helou, University of California San Francisco; Krishna Shrinivas, Harvard University; Jen Liou, Univ Texas Southwestern Med Ctr Dallas; Byron Au-Yeung, Emory University; Arthur Weiss, University of California San Francisco
• Language: English
• Date: 2022-12-29
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41590-022-01372-2
• Title of Journal or Parent Work: NATURE IMMUNOLOGY
• Volume: 24
• Issue: 1
• Start Page: 136
• End Page: 147
• Grant/Funding Information: 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).
• Keywords: Life Sciences & Biomedicine; Science & Technology; ANTIGEN RECEPTOR; SELECTION; EXPRESSION; THYMOCYTES; Immunology; FAMILY; MUTATION; HOMEOSTASIS; ACTIVATION; INOSITOL; TURNOVER
• Research Categories: Mathematics

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.