期刊
IMMUNITY
卷 54, 期 8, 页码 1698-+出版社
CELL PRESS
DOI: 10.1016/j.immuni.2021.06.007
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资金
- National Health and Medical Research Council (NHMRC) [1085151, 1139607, 2003942]
- Swiss National Science Foundation
- Novartis Foundation for Medical-Biological Research
- University of Queensland, a NHMRC of Australia [1140406]
- Cure Cancer Australia with the assistance of Cancer Australia [1158085]
- Melanoma Research Alliance (USA), the Cancer Council of Victoria [1145730]
- NHMRC [1124907, 1124784, 1124788]
- Walter and Eliza Hall Institute Centenary Fellowship - CSL Ltd
- National University of Colombia
- Elite Network of Bavaria (Germany)
- National Health and Medical Research Council of Australia [1139607, 1085151, 1124788, 1124784, 1124907] Funding Source: NHMRC
Research demonstrates that in chronic viral infections and tumors, Tpex cells maintain long-term functionality by sustaining mitochondrial health and suppressing mTOR signaling, with transforming growth factor-beta playing a critical role in Tpex cell metabolism and function.
Antigen-specific CD8(+) T cells in chronic viral infections and tumors functionally deteriorate, a process known as exhaustion. Exhausted T cells are sustained by precursors of exhausted (Tpex) cells that self-renew while continuously generating exhausted effector (Tex) cells. However, it remains unknown how Tpex cells maintain their functionality. Here, we demonstrate that Tpex cells sustained mitochondrial fitness, including high spare respiratory capacity, while Tex cells deteriorated metabolically over time. Tpex cells showed early suppression of mTOR kinase signaling but retained the ability to activate this pathway in response to antigen receptor signals. Early transient mTOR inhibition improved long-term T cell responses and checkpoint inhibition. Transforming growth factor-beta repressed mTOR signaling in exhausted T cells and was a critical determinant of Tpex cell metabolism and function. Overall, we demonstrate that the preservation of cellular metabolism allows Tpex cells to retain long-term functionality to sustain T cell responses during chronic infection.
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