Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-dependent autoimmunity
Evan R. Abt, … , Ting-Ting Wu, Caius G. Radu
Evan R. Abt, … , Ting-Ting Wu, Caius G. Radu
Published June 2, 2022
Citation Information: J Clin Invest. 2022. https://doi.org/10.1172/JCI160852.
View: Text | PDF
Research In-Press Preview Immunology Metabolism

Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-dependent autoimmunity

Abstract

Purine nucleoside phosphorylase (PNP) enables the breakdown and recycling of guanine nucleosides. PNP insufficiency in humans is paradoxically associated with both immunodeficiency and autoimmunity, but the mechanistic basis for these outcomes is incompletely understood. Here we identify two immune lineage-dependent consequences of PNP inactivation dictated by distinct gene interactions. During T cell development, PNP inactivation is synthetically lethal with down-regulation of the dNTP triphosphohydrolase SAMHD1. This interaction requires deoxycytidine kinase activity and is antagonized by microenvironmental deoxycytidine. In B lymphocytes and macrophages, PNP regulates Toll like receptor 7 signaling by controlling the levels of its (deoxy)guanosine nucleoside ligands. Overriding this regulatory mechanism promotes germinal center formation in the absence of exogenous antigen and accelerates disease in a mouse model of autoimmunity. This work reveals that one purine metabolism gene protects against immunodeficiency and autoimmunity via independent mechanisms operating in distinct immune lineages and identifies PNP as a novel metabolic immune checkpoint.

Authors

Evan R. Abt, Khalid Rashid, Thuc M. Le, Suwen Li, Hailey R. Lee, Vincent Lok, Luyi Li, Amanda L. Creech, Amanda N. Labora, Hanna K. Mandl, Alex K. Lam, Arthur Cho, Valerie Rezek, Nanping Wu, Gabriel Abril-Rodriguez, Ethan W. Rosser, Steven D. Mittelman, Willy Hugo, Thomas Mehrling, Shanta Bantia, Antoni Ribas, Timothy R. Donahue, Gay M. Crooks, Ting-Ting Wu, Caius G. Radu

×
Problems with a PDF?

This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.

Having trouble reading a PDF?

PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.

Having trouble saving a PDF?

Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.

Having trouble printing a PDF?

  1. Try printing one page at a time or to a newer printer.
  2. Try saving the file to disk before printing rather than opening it "on the fly." This requires that you configure your browser to "Save" rather than "Launch Application" for the file type "application/pdf", and can usually be done in the "Helper Applications" options.
  3. Make sure you are using the latest version of Adobe's Acrobat Reader.

- Download (13.04 MB)

Advertisement