Purine Nucleoside Phosphorylase Enables Dual Metabolic Checkpoints That Prevent T Cell Immunodeficiency and TLR7-associated Autoimmunity

Overview

Journal J Clin Invest

Specialty General Medicine

Date 2022 Jun 2

PMID 35653193

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

Affiliations

Soon will be listed here.

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 downregulation 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 potentially novel metabolic immune checkpoint.

Citing Articles

SAMHD1 shapes deoxynucleotide triphosphate homeostasis by interconnecting the depletion and biosynthesis of different dNTPs.

McCown C, Yu C, Ivanov D Nat Commun. 2025; 16(1):793.

PMID: 39824836 PMC: 11742054. DOI: 10.1038/s41467-025-56208-y.

D-ribose-5-phosphate inactivates YAP and functions as a metabolic checkpoint.

Tu C, Liu Y, Liu H, Jiao C, Liu Q, Hung M J Hematol Oncol. 2025; 18(1):2.

PMID: 39755622 PMC: 11700446. DOI: 10.1186/s13045-024-01655-1.

Candidate Genetic Loci Modifying the Colorectal Cancer Risk Caused by Lifestyle Risk Factors.

Barot S, Vermani L, Blom J, Larsson S, Liljegren A, Lindblom A Clin Transl Gastroenterol. 2024; 16(1):e00790.

PMID: 39665592 PMC: 11756881. DOI: 10.14309/ctg.0000000000000790.

Ecological diversification of sea catfishes is accompanied by genome-wide signatures of positive selection.

Rincon-Sandoval M, De-Kayne R, Shank S, Pirro S, Koou A, Abueg L Nat Commun. 2024; 15(1):10040.

PMID: 39567489 PMC: 11579386. DOI: 10.1038/s41467-024-54184-3.

Understanding the interplay between dNTP metabolism and genome stability in cancer.

Yague-Capilla M, Rudd S Dis Model Mech. 2024; 17(8).

PMID: 39206868 PMC: 11381932. DOI: 10.1242/dmm.050775.

References

Sun V, Sharpley M, Kaczor-Urbanowicz K, Chang P, Montel-Hagen A, Lopez S . The Metabolic Landscape of Thymic T Cell Development and . Front Immunol. 2021; 12:716661. PMC: 8355594. DOI: 10.3389/fimmu.2021.716661. View

Kim W, Le T, Wei L, Poddar S, Bazzy J, Wang X . [18F]CFA as a clinically translatable probe for PET imaging of deoxycytidine kinase activity. Proc Natl Acad Sci U S A. 2016; 113(15):4027-32. PMC: 4839461. DOI: 10.1073/pnas.1524212113. View

Lewers J, Ceballos-Picot I, Shirley T, Mockel L, Egami K, Jinnah H . Consequences of impaired purine recycling in dopaminergic neurons. Neuroscience. 2008; 152(3):761-72. PMC: 3498629. DOI: 10.1016/j.neuroscience.2007.10.065. View

Le T, Poddar S, Capri J, Abt E, Kim W, Wei L . ATR inhibition facilitates targeting of leukemia dependence on convergent nucleotide biosynthetic pathways. Nat Commun. 2017; 8(1):241. PMC: 5556071. DOI: 10.1038/s41467-017-00221-3. View

Davenne T, Klintman J, Sharma S, Rigby R, Blest H, Cursi C . SAMHD1 Limits the Efficacy of Forodesine in Leukemia by Protecting Cells against the Cytotoxicity of dGTP. Cell Rep. 2020; 31(6):107640. PMC: 7225753. DOI: 10.1016/j.celrep.2020.107640. View

Shlomchik M, Madaio M, Ni D, Trounstein M, Huszar D . The role of B cells in lpr/lpr-induced autoimmunity. J Exp Med. 1994; 180(4):1295-306. PMC: 2191708. DOI: 10.1084/jem.180.4.1295. View

Dominguez-Villar M, Hafler D . Regulatory T cells in autoimmune disease. Nat Immunol. 2018; 19(7):665-673. PMC: 7882196. DOI: 10.1038/s41590-018-0120-4. View

Arpaia E, Benveniste P, Di Cristofano A, Gu Y, Dalal I, Kelly S . Mitochondrial basis for immune deficiency. Evidence from purine nucleoside phosphorylase-deficient mice. J Exp Med. 2000; 191(12):2197-208. PMC: 2193200. DOI: 10.1084/jem.191.12.2197. View

Arkatkar T, Du S, Jacobs H, Dam E, Hou B, Buckner J . B cell-derived IL-6 initiates spontaneous germinal center formation during systemic autoimmunity. J Exp Med. 2017; 214(11):3207-3217. PMC: 5679179. DOI: 10.1084/jem.20170580. View

10.

Herrmann A, Wittmann S, Thomas D, Shepard C, Kim B, Ferreiros N . The SAMHD1-mediated block of LINE-1 retroelements is regulated by phosphorylation. Mob DNA. 2018; 9:11. PMC: 5872582. DOI: 10.1186/s13100-018-0116-5. View

11.

Vareed S, Bhat V, Thompson C, Vasu V, Fermin D, Choi H . Metabolites of purine nucleoside phosphorylase (NP) in serum have the potential to delineate pancreatic adenocarcinoma. PLoS One. 2011; 6(3):e17177. PMC: 3063153. DOI: 10.1371/journal.pone.0017177. View

12.

Ghandi M, Huang F, Jane-Valbuena J, Kryukov G, Lo C, McDonald 3rd E . Next-generation characterization of the Cancer Cell Line Encyclopedia. Nature. 2019; 569(7757):503-508. PMC: 6697103. DOI: 10.1038/s41586-019-1186-3. View

13.

Baenziger S, Heikenwalder M, Johansen P, Schlaepfer E, Hofer U, Miller R . Triggering TLR7 in mice induces immune activation and lymphoid system disruption, resembling HIV-mediated pathology. Blood. 2008; 113(2):377-88. DOI: 10.1182/blood-2008-04-151712. View

14.

Uhlen M, Karlsson M, Zhong W, Tebani A, Pou C, Mikes J . A genome-wide transcriptomic analysis of protein-coding genes in human blood cells. Science. 2019; 366(6472). DOI: 10.1126/science.aax9198. View

15.

Abt E, Le T, Dann A, Capri J, Poddar S, Lok V . Reprogramming of nucleotide metabolism by interferon confers dependence on the replication stress response pathway in pancreatic cancer cells. Cell Rep. 2022; 38(2):110236. PMC: 8893345. DOI: 10.1016/j.celrep.2021.110236. View

16.

Bantia S, Parker C, Upshaw R, Cunningham A, Kotian P, Kilpatrick J . Potent orally bioavailable purine nucleoside phosphorylase inhibitor BCX-4208 induces apoptosis in B- and T-lymphocytes--a novel treatment approach for autoimmune diseases, organ transplantation and hematologic malignancies. Int Immunopharmacol. 2010; 10(7):784-90. DOI: 10.1016/j.intimp.2010.04.009. View

17.

Liu X, Jin S, Hu S, Li R, Pan H, Liu Y . Single-cell transcriptomics links malignant T cells to the tumor immune landscape in cutaneous T cell lymphoma. Nat Commun. 2022; 13(1):1158. PMC: 8894386. DOI: 10.1038/s41467-022-28799-3. View

18.

Ariav Y, Chng J, Christofk H, Ron-Harel N, Erez A . Targeting nucleotide metabolism as the nexus of viral infections, cancer, and the immune response. Sci Adv. 2021; 7(21). PMC: 8133749. DOI: 10.1126/sciadv.abg6165. View

19.

Tanji H, Ohto U, Shibata T, Taoka M, Yamauchi Y, Isobe T . Toll-like receptor 8 senses degradation products of single-stranded RNA. Nat Struct Mol Biol. 2015; 22(2):109-15. DOI: 10.1038/nsmb.2943. View

20.

Mansouri A, Min W, Cole C, Josselyn S, Henderson J, van Eede M . Cerebellar abnormalities in purine nucleoside phosphorylase deficient mice. Neurobiol Dis. 2012; 47(2):201-9. DOI: 10.1016/j.nbd.2012.04.001. View