Inosine is an alternative carbon supply that supports effector T cell proliferation and anti-tumor function under glucose restriction

T cells undergo a characteristic metabolic rewiring that fulfills the dramatically increased bioenergetic, biosynthetic, and redox demands following antigen stimulation. A robust adaptive immune system requires effector T cells to respond and adapt to fluctuations in environmental nutrient levels im...

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Published inbioRxiv
Main Authors Wang, Tingting, Jn Rashida Gnanaprakasam, Chen, Xuyong, Kang, Siwen, Xu, Xuequn, Sun, Hua, Liu, Lingling, Miller, Ethan, Cassel, Teresa A, Sun, Qiushi, Vicente-Munoz, Sara, Warmoes, Marc O, Lane, Andrew N, Song, Xiaotong, Fan, Teresa W-M, Wang, Ruoning
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 14.09.2019
Subjects
Antitumor activity
Bioenergetics
Cell growth
Cell proliferation
Effector cells
Glucose
Hypoxanthine
Immune checkpoint
Immune system
Inflammation
Lymphocytes
Lymphocytes T
Metabolic pathways
Metabolism
Metabolomics
Phosphorylase
Ribose
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Summary:T cells undergo a characteristic metabolic rewiring that fulfills the dramatically increased bioenergetic, biosynthetic, and redox demands following antigen stimulation. A robust adaptive immune system requires effector T cells to respond and adapt to fluctuations in environmental nutrient levels imposed by infectious and inflammatory sites in different tissues. Inevitably, such responsiveness and adaptation reflect metabolic plasticity, allowing T cells to elicit immune functions by using a wide range of nutrient substrates. Here, we show that effector T cells utilize inosine, as an alternative substrate, to support cell growth and function in the absence of glucose. T cells metabolize inosine into hypoxanthine and phosphorylated ribose by purine nucleoside phosphorylase (PNP). Using Stable Isotope-Resolved Metabolomics (SIRM), we demonstrated that ribose moiety of inosine can enter into central metabolic pathways to provide ATP and biosynthetic precursors. Accordingly, the dependence of T cells on extracellular glucose for growth and effector functions can be relieved by inosine. On the other hand, cancer cells display diverse capacity to utilize inosine as a carbon resource. Moreover, the supplement of inosine enhances the anti-tumor efficacy of immune-checkpoint blockade or adoptive T cell transfer, reflecting the capability of inosine in relieving tumor-imposed metabolic restrictions on T cells in vivo.
DOI:10.1101/766642