Determining how nucleoside metabolism regulates contrasting immune functions in the rare disease PNP deficiency

FINDINGS

The metabolic enzyme purine nucleoside phosphorylase (PNP) protects against immunodeficiency and regulates innate immune signaling via previously unknown and independent mechanisms. The results inform the design of approaches to treat PNP insufficiency in humans as well as new therapeutic applications for clinical-stage PNP inhibitors. The study is published online ahead of print in the Journal of Clinical Investigation.

BACKGROUND

The enzyme PNP enables the breakdown and recycling of guanine nucleoside metabolites. PNP deficiency is a rare heritable disease characterized by immune abnormalities that manifest as both immunodeficiency and autoimmunity. In this study, the authors sought to understand the mechanisms contributing to these seemingly paradoxical outcomes.

METHODS

The authors applied a model of immune cell development, mass spectrometry-based metabolite tracing, single-cell transcriptomic analyses and a selective inhibitor of deoxycytidine kinase developed in the laboratory of Dr. Caius Radu at UCLA Jonsson Comprehensive Cancer Center.

IMPACT

The study provides mechanistic insight into the immunoregulatory functions of PNP and explains one of the enduring mysteries regarding the mechanisms responsible for T-cell immunodeficiency in patients with PNP-inactivating mutations. It further reveals that PNP functions as a metabolic immune checkpoint that restricts activity of the innate immune sensor Toll-like receptor 7.

EXPERT COMMENTS

“This study highlights two independent mechanisms by which one metabolism gene supports immune function,” said first author Evan Abt, a postdoctoral researcher in the Department of Molecular and Medical Pharmacology at UCLA. “This highly collaborative project reflects the contributions of a team of researchers with diverse but complementary expertise and leverages several innovative technologies developed at UCLA.”

Radu, a research scientist with the UCLA Jonsson Comprehensive Cancer Center and a professor of molecular and medical pharmacology, added: “Importantly, in addition to providing insights for future research, our findings also inform a potential therapeutic approach for patients with PNP deficiency and suggest a new application for clinical-stage PNP inhibitors to enhance innate immune signaling.”

AUTHORS

First co-authors Evan Abt, Khalid Rashid and Thuc Le are UCLA researchers, as are Suwen Li, Hailey Lee, Vincent Lok, Luyi Li, Amanda Creech, Amanda Labora, Hanna Mandl, Alex Lam, Valerie Rezek, Nanping Wu, Gabriel Abril-Rodriguez, Ethan Rosser, Steven Mittelman, Willy Hugo, Timothy Donahue, Gay Crooks, Ting-Ting Wu, and corresponding author Caius Radu. UCLA researcher Dr. Antoni Ribas is also with the Parker Institute for Cancer Immunotherapy in San Francisco. Additional authors are Arthur Cho of Yonsei University in South Korea and Thomas Mehrling and Shanta Bantia of Laevoroc Oncology in Switzerland.