PIK3IP1/TrIP restricts activation of T cells through inhibition of PI3K/Akt

J Exp Med. 2018 Dec 3;215(12):3165-3179. doi: 10.1084/jem.20172018. Epub 2018 Nov 14.


Phosphatidylinositol-3 kinases (PI3Ks) modulate cellular growth, proliferation, and survival; dysregulation of the PI3K pathway can lead to autoimmune disease and cancer. PIK3IP1 (or transmembrane inhibitor of PI3K [TrIP]) is a putative transmembrane regulator of PI3K. TrIP contains an extracellular kringle domain and an intracellular domain with homology to the inter-SH2 domain of the PI3K regulatory subunit p85, but the mechanism of TrIP function is poorly understood. We show that both the kringle and p85-like domains are necessary for TrIP inhibition of PI3K and that TrIP is down-modulated from the surface of T cells during T cell activation. In addition, we present evidence that the kringle domain may modulate TrIP function by mediating oligomerization. Using an inducible knockout mouse model, we show that TrIP-deficient T cells exhibit more robust activation and can mediate clearance of Listeria monocytogenes infection faster than WT mice. Thus, TrIP is a negative regulator of T cell activation and may represent a novel target for immune modulation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / immunology*
  • Class Ia Phosphatidylinositol 3-Kinase / genetics
  • Class Ia Phosphatidylinositol 3-Kinase / immunology*
  • HEK293 Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Listeria monocytogenes / immunology
  • Listeriosis / genetics
  • Listeriosis / immunology
  • Listeriosis / pathology
  • Lymphocyte Activation*
  • Membrane Proteins
  • Mice
  • Mice, Transgenic
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / pathology


  • Carrier Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Pik3ip1 protein, mouse
  • Class Ia Phosphatidylinositol 3-Kinase