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 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.
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Tingting Wang (edit)
JN Rashida Gnanaprakasam (add twitter)
Xuyong Chen (add twitter)
Siwen Kang (add twitter)
Xuequn Xu (add twitter)
Hua Sun (edit)
Lingling Liu (add twitter)
Ethan Miller (edit)
Teresa A. Cassel (add twitter)
Qiushi Sun (add twitter)
Sara Vicente-Munoz (add twitter)
Marc O. Warmoes (add twitter)
Andrew N. Lane (add twitter)
Xiaotong Song (add twitter)
Teresa W.-M. Fan (add twitter)
Ruoning Wang (edit)
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Immunology

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09/14/19 02:02AM
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