Equilibrative Nucleoside Transporter 3 Regulates T Cell Homeostasis by Coordinating Lysosomal Function with Nucleoside Availability

Publication date: 22 May 2018
Source:Cell Reports, Volume 23, Issue 8
Author(s): Chin-Wen Wei, Chia-Ying Lee, Ding-Jin Lee, Chang-Feng Chu, Ju-Chu Wang, Tien-Chiao Wang, Wann-Neng Jane, Zee-Fen Chang, Chuen-Miin Leu, Ivan L. Dzhagalov, Chia-Lin Hsu
T cells are a versatile immune cell population responding to challenges by differentiation and proliferation followed by contraction and memory formation. Dynamic metabolic reprogramming is essential for T cells to meet the biosynthetic needs and the reutilization of biomolecules, processes that require active participation of metabolite transporters. Here, we show that equilibrative nucleoside transporter 3 (ENT3) is highly expressed in peripheral T cells and has a key role in maintaining T cell homeostasis by supporting the proliferation and survival of T cells. ENT3 deficiency leads to an enlarged and disturbed lysosomal compartment, resulting in accumulation of surplus mitochondria, elevation of intracellular reactive oxygen species, and DNA damage in T cells. Our results identify ENT3 as a vital metabolite transporter that supports T cell homeostasis and activation by regulating lysosomal integrity and the availability of nucleosides. Moreover, we uncovered that T cell lysosomes are an important source of salvaged metabolites for survival and proliferation.

Graphical abstract

Teaser

A sufficient supply of biomaterials is essential during T cell differentiation and proliferation. Wei et al. reveal that the nucleoside transporter ENT3 is necessary for maintaining T cell homeostasis and survival by regulating lysosome function and nucleoside availability.


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