Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-associated 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 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.

Single-Cell Metabolomics-Based Strategy for Studying the Mechanisms of Drug Action

“…These mononucleotides are further hydrolyzed by nucleosidases to nucleosides, which undergo phosphorolysis by nucleoside phosphorylase to yield nucleobases. PNP is an enzyme involved in purine metabolism, which can metabolize nucleosides into nucleobases . The results of the western blot showed that the content of PNP in gefitinib treatment group was significantly disordered (Figure S7D,E), which led to the disorder of nucleosides and nucleobases.…”

“…PNP is an enzyme involved in purine metabolism, which can metabolize nucleosides into nucleobases. 39 The results of the western blot showed that the content of PNP in gefitinib treatment group was significantly disordered (Figure S7D,E), which led to the disorder of nucleosides and nucleobases. In addition, nucleobases can be reused to synthesize nucleotides, which is only a remedial synthetic pathway for intracellular nucleotides.…”

Spatially resolved metabolomics and isotope tracing reveal dynamic metabolic responses of dentate granule neurons with acute stimulation

“…Inosine to R1P metabolism via PNP has clear importance in other biological contexts. PNP is established as an essential player in lymphocyte metabolism, and inosine can even completely substitute for glucose in fueling effector T cells in vitro 49,50 . On the clinical side, the PNP inhibitor forodesine is currently in a variety of clinical trials as a possible treatment for lymphomas (https://www.clinicaltrials.gov/ct2/ results?…”

Immunodeficiency and autoimmunity: companions not opposites

“…In this issue of the JCI , a report by Abt and colleagues explored the consequences of deficiency of the enzyme purine nucleoside phosphorylase (PNP) ( 8 ). The authors used synthetic inhibitors of PNP to clarify the pathway through which PNP deficiency is toxic to developing T cells and also propose a mechanism for the association of PNP deficiency with autoimmunity through effects on TLR7.…”

“…Increased formation of germinal centers also occurred, even in the absence of immunization with exogenous antigen. In MRL-LPR mice, which are prone to developing autoimmunity, acceleration of lymphoproliferative and lupus-like autoimmunity was observed with five weeks of exposure to a PNP inhibitor ( 8 ). Further work is needed to more fully understand how the accumulation of purine nucleosides alters the consequences of TLR7 engagement, the full range of cell types in which these interactions occur, and which cytokines, other than IL-6, play roles in the acceleration of autoimmunity by PNP inhibitors.…”