[en] UV radiation resistance-associated gene (UVRAG) encodes a tumor suppressor with putative roles in autophagy, endocytic trafficking, and DNA damage repair but its in vivo role in T cells is unknown. Because conditional homozygous deletion of Uvrag in mice results in early embryonic lethality, we generated T-cell-specific UVRAG-deficient mice that lacked UVRAG expression specifically in T cells. This loss of UVRAG led to defects in peripheral homeostasis that could not be explained by the increased sensitivity to cell death and impaired proliferation observed for other autophagy-related gene knockout mice. Instead, UVRAG-deficient T-cells exhibited normal mitochondrial clearance and activation-induced autophagy, suggesting that UVRAG has an autophagy-independent role that is critical for peripheral naive T-cell homeostatic proliferation. In vivo, T-cell-specific loss of UVRAG dampened CD8(+) T-cell responses to LCMV infection in mice, delayed viral clearance, and impaired memory T-cell generation. Our data provide novel insights into the control of autophagy in T cells and identify UVRAG as a new regulator of naïve peripheral T-cell homeostasis.
Disciplines :
Immunology & infectious disease
Author, co-author :
Afzal, Samia; Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5S 1A8, Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1
Hao, Zhenyue; Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1
Itsumi, Momoe; Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1, Department of Urology, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka. 812-8582, Japan
Abouelkheer, Yasser; Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1
BRENNER, Dirk ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Immunology and Genetics
Gao, Yunfei; Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1
Wakeham, Andrew; Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1
Hong, Claire; Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1
Li, Wanda Y; Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1
Sylvester, Jennifer; Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1
Gilani, Syed O; Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1
Brüstle, Anne; Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1, Pathogens and Immunity Department, Australian National University, Acton Act 2601, Canberra, Australia
Haight, Jillian; Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1
You-Ten, Annick J; Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1
Lin, Gloria H Y; Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1
Inoue, Satoshi; Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1
Mak, Tak W; Department of Immunology, University of Toronto, Toronto, Ontario, Canada M5S 1A8, Campbell Family Cancer Research Institute, University Health Network, Toronto, Ontario, Canada M5G 2C1, tmak@uhnres.utoronto.ca
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