PT  - JOURNAL ARTICLE
AU  - Tingting Wang
AU  - JN Rashida Gnanaprakasam
AU  - Xuyong Chen
AU  - Siwen Kang
AU  - Xuequn Xu
AU  - Hua Sun
AU  - Lingling Liu
AU  - Ethan Miller
AU  - Teresa A. Cassel
AU  - Qiushi Sun
AU  - Sara Vicente-Muñoz
AU  - Marc O. Warmoes
AU  - Andrew N. Lane
AU  - Xiaotong Song
AU  - Teresa W.-M. Fan
AU  - Ruoning Wang
TI  - Inosine is an alternative carbon supply that supports effector T cell proliferation and antitumor function under glucose restriction
AID  - 10.1101/766642
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 766642
4099  - http://biorxiv.org/content/early/2019/09/14/766642.short
4100  - http://biorxiv.org/content/early/2019/09/14/766642.full
AB  - 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.