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

Uzodinma U Uche1,2, Ann R Piccirillo1, Shunsuke Kataoka3

  • 1Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA.

The Journal of Experimental Medicine
|November 16, 2018
PubMed

Insights

Transmembrane inhibitor of PI3K (TrIP) negatively regulates T cell activation. TrIP deficiency enhances T cell responses and improves Listeria monocytogenes infection clearance in mice.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Biology

Background:

  • Phosphatidylinositol-3 kinases (PI3Ks) are crucial for cellular processes, with dysregulation linked to cancer and autoimmune diseases.
  • PIK3IP1, also known as transmembrane inhibitor of PI3K (TrIP), is a transmembrane protein potentially regulating PI3K.
  • The precise mechanism of TrIP function, particularly its structural domains' roles, remains largely undefined.

Purpose of the Study:

  • To elucidate the functional mechanism of TrIP in PI3K regulation and T cell activation.
  • To investigate the roles of TrIP's extracellular kringle and intracellular p85-homology domains.
  • To determine TrIP's impact on T cell activation and immune response in vivo.

Main Methods:

  • Functional assays to assess the necessity of TrIP domains for PI3K inhibition.
  • Analysis of TrIP surface expression on T cells during activation.
  • Investigation of TrIP-mediated oligomerization via its kringle domain.
  • Utilizing an inducible knockout mouse model to study TrIP-deficient T cell responses and infection clearance.

Main Results:

  • Both the kringle and p85-like domains of TrIP are essential for PI3K inhibition.
  • TrIP expression is reduced on the surface of activated T cells.
  • Evidence suggests the kringle domain mediates TrIP oligomerization, influencing its function.
  • TrIP-deficient T cells display heightened activation and accelerated clearance of Listeria monocytogenes infection.

Conclusions:

  • TrIP acts as a negative regulator of T cell activation.
  • TrIP's domains are critical for its inhibitory function.
  • TrIP modulation of T cell activation suggests it as a potential therapeutic target for immune modulation.

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