@article{3626df478e794694bd98203e339f81b4,
title = "Transforming growth factor-β-regulated mTOR activity preserves cellular metabolism to maintain long-term T cell responses in chronic infection",
abstract = "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-β 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.",
keywords = "checkpoint inhibition, mitochondria, OXPHOS, precursors of exhausted T cells, progenitor T cells, rapamycin, stem-like T cells, T cell exhaustion, T cell function, TCF1",
author = "Gabriel, {Sarah S.} and Carlson Tsui and David Chisanga and Flora Weber and Manuela Llano-Le{\'o}n and Gubser, {Patrick M.} and Laurent Bartholin and Fernando Souza-Fonseca-Guimaraes and Huntington, {Nicholas D.} and Wei Shi and Utzschneider, {Daniel T.} and Axel Kallies",
note = "Funding Information: We thank Teisha Mason for technical support and members of the Kallies lab and Sammy Bedoui for discussions. This work was funded by the National Health and Medical Research Council (NHMRC, project grant no. 1085151 and fellowship no. 1139607 [to A.K.] and ideas grant no. 2003942 [to S.G.]), the Swiss National Science Foundation (fellowships to S.S.G. P.M.G. and D.T.U.), and the Novartis Foundation for Medical-Biological Research (fellowship to S.S.G.). D.T.U. is a Special Fellow of The Leukemia & Lymphoma Society. F.S.-F.-G. is funded by the University of Queensland, a NHMRC of Australia grant (1140406), and a grant awarded through the Priority-driven Collaborative Cancer Research Scheme and funded by Cure Cancer Australia with the assistance of Cancer Australia (1158085). N.D.H. is funded by the Melanoma Research Alliance (USA), the Cancer Council of Victoria (1145730), and the NHMRC (1124907, 1124784, and 1124788). W.S. is funded by a Walter and Eliza Hall Institute Centenary Fellowship funded by a donation from CSL Ltd. The internship of M.L.-L. was funded by the National University of Colombia, and F.W. was supported by the Elite Network of Bavaria (Germany). We acknowledge the Melbourne Cytometry Platform for the provision of flow cytometry services and the NIH Tetramer Facility for providing tetramers. S.S.G. D.T.U. and A.K. conceived the study, designed the experiments, interpreted the results, and wrote the paper. S.S.G. and D.T.U. performed the experiments, with support from C.T. F.W. M.L.-L. and P.M.G. D.C. and W.S. analyzed the sequencing data, and L.B. F.S.-F.-G. and N.D.H. provided mice critical to this study. F.S.-F.-G. has a funded research collaborative agreement with Miltenyi Biotec Australia and is a consultant for Biotheus. N.D.H. is founder and shareholder of oNKo-Innate Pty Ltd. The authors declare no other competing interests. Funding Information: We thank Teisha Mason for technical support and members of the Kallies lab and Sammy Bedoui for discussions. This work was funded by the National Health and Medical Research Council (NHMRC, project grant no. 1085151 and fellowship no. 1139607 [to A.K.] and ideas grant no. 2003942 [to S.G.]), the Swiss National Science Foundation (fellowships to S.S.G., P.M.G., and D.T.U.), and the Novartis Foundation for Medical-Biological Research (fellowship to S.S.G.). D.T.U. is a Special Fellow of The Leukemia & Lymphoma Society. F.S.-F.-G. is funded by the University of Queensland , a NHMRC of Australia grant ( 1140406 ), and a grant awarded through the Priority-driven Collaborative Cancer Research Scheme and funded by Cure Cancer Australia with the assistance of Cancer Australia ( 1158085 ). N.D.H. is funded by the Melanoma Research Alliance (USA), the Cancer Council of Victoria ( 1145730 ), and the NHMRC ( 1124907 , 1124784 , and 1124788 ). W.S. is funded by a Walter and Eliza Hall Institute Centenary Fellowship funded by a donation from CSL Ltd. The internship of M.L.-L. was funded by the National University of Colombia, and F.W. was supported by the Elite Network of Bavaria (Germany). We acknowledge the Melbourne Cytometry Platform for the provision of flow cytometry services and the NIH Tetramer Facility for providing tetramers. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = aug,
day = "10",
doi = "10.1016/j.immuni.2021.06.007",
language = "English",
volume = "54",
pages = "1698--1714.e5",
journal = "Immunity",
issn = "1074-7613",
publisher = "Elsevier",
number = "8",
}
