Please use this identifier to cite or link to this item:
Title: Transforming growth factor-β-regulated mTOR activity preserves cellular metabolism to maintain long-term T cell responses in chronic infection.
Austin Authors: Gabriel, Sarah S;Tsui, Carlson;Chisanga, David;Weber, Flora;Llano-León, Manuela;Gubser, Patrick M;Bartholin, Laurent;Souza-Fonseca-Guimaraes, Fernando;Huntington, Nicholas D;Shi, Wei;Utzschneider, Daniel T;Kallies, Axel
Affiliation: INSERM U1052, Centre de Recherche en Cancérologie de Lyon, 69000 Lyon, France
School of Cancer Medicine, La Trobe University, Heidelberg, VIC, Australia
School of Computing and Information Systems, University of Melbourne, Melbourne, VIC, Australia
Department of Microbiology and Immunology, The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Melbourne, VIC, Australia
University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia
Biomedicine Discovery Institute and the Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
Olivia Newton-John Cancer Research Institute
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia
Department of Medical Biology, University of Melbourne, Melbourne, VIC, Australia
Issue Date: 10-Aug-2021 2021-06-29
Publication information: Immunity 2021; 54(8): 1698-1714.e5
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.
DOI: 10.1016/j.immuni.2021.06.007
Journal: Immunity
PubMed URL: 34233154
Type: Journal Article
Subjects: OXPHOS
T cell exhaustion
T cell function
checkpoint inhibition
precursors of exhausted T cells
progenitor T cells
stem-like T cells
Appears in Collections:Journal articles

Show full item record

Page view(s)

checked on Jun 9, 2023

Google ScholarTM


Items in AHRO are protected by copyright, with all rights reserved, unless otherwise indicated.