RT Journal Article
SR Electronic
T1 Inosine is an alternative carbon supply that supports effector T cell proliferation and antitumor function under glucose restriction
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 766642
DO 10.1101/766642
A1 Tingting Wang
A1 JN Rashida Gnanaprakasam
A1 Xuyong Chen
A1 Siwen Kang
A1 Xuequn Xu
A1 Hua Sun
A1 Lingling Liu
A1 Ethan Miller
A1 Teresa A. Cassel
A1 Qiushi Sun
A1 Sara Vicente-Muñoz
A1 Marc O. Warmoes
A1 Andrew N. Lane
A1 Xiaotong Song
A1 Teresa W.-M. Fan
A1 Ruoning Wang
YR 2019
UL http://biorxiv.org/content/early/2019/09/14/766642.abstract
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.