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

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

Author information

1
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
2
Interdisciplinary Biomedical Graduate Program, University of Pittsburgh School of Medicine, Pittsburgh, PA.
3
Asahi Kasei Pharma Corporation, Tokyo, Japan.
4
Graduate Program in Microbiology and Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
5
Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA lkane@pitt.edu.

Abstract

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.

PMID:
30429249
PMCID:
PMC6279406
[Available on 2019-06-03]
DOI:
10.1084/jem.20172018

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