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

• Published in: The Journal of experimental medicine Vol. 215; no. 12; pp. 3165 - 3179
• Main Authors: Uche, Uzodinma U, Piccirillo, Ann R, Kataoka, Shunsuke, Grebinoski, Stephanie J, D'Cruz, Louise M, Kane, Lawrence P
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 03.12.2018
• Subjects: 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
• DOI: 10.1084/jem.20172018
• ISSN: 0022-1007

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 infection faster than WT mice. Thus, TrIP is a negative regulator of T cell activation and may represent a novel target for immune modulation.