Transforming growth factor-β-regulated mTOR activity preserves cellular metabolism to maintain long-term T cell responses in chronic infection - PubMed (original) (raw)

. 2021 Aug 10;54(8):1698-1714.e5.

doi: 10.1016/j.immuni.2021.06.007. Epub 2021 Jul 6.

Carlson Tsui 1, David Chisanga 2, Flora Weber 1, Manuela Llano-León 1, Patrick M Gubser 1, Laurent Bartholin 3, Fernando Souza-Fonseca-Guimaraes 4, Nicholas D Huntington 5, Wei Shi 6, Daniel T Utzschneider 7, Axel Kallies 8

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Transforming growth factor-β-regulated mTOR activity preserves cellular metabolism to maintain long-term T cell responses in chronic infection

Sarah S Gabriel et al. Immunity. 2021.

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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: OXPHOS; T cell exhaustion; T cell function; TCF1; checkpoint inhibition; mitochondria; precursors of exhausted T cells; progenitor T cells; rapamycin; stem-like T cells.

Copyright © 2021 Elsevier Inc. All rights reserved.

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Conflict of interest statement

Declaration of interests 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.

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