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Sustained CD28 costimulation is required for self-renewal and differentiation of TCF-1+ PD-1+ CD8 T cells

During persistent antigen stimulation, such as in chronic infections and cancer, CD8 T cells differentiate into a hypofunctional programmed death protein 1-positive (PD-1+) exhausted state. Exhausted CD8 T cell responses are maintained by precursors (Tpex) that express the transcription factor T cel...

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Main Authors: Humblin, Etienne (Author) , Korpas, Isabel (Author) , Lu, Jiahua (Author) , Filipescu, Dan (Author) , van der Heide, Verena (Author) , Goldstein, Simon (Author) , Vaidya, Abishek (Author) , Soares-Schanoski, Alessandra (Author) , Casati, Beatrice (Author) , Selvan, Myvizhi E. (Author) , Gümüş, Zeynep H. (Author) , Wieland, Andreas (Author) , Corrado, Mauro (Author) , Cohen-Gould, Leona (Author) , Bernstein, Emily (Author) , Homann, Dirk (Author) , Chipuk, Jerry (Author) , Kamphorst, Alice O. (Author)
Format: Article (Journal)
Language:English
Published: August 25, 2023
In: Science immunology
Year: 2023, Volume: 8, Issue: 86, Pages: 1-13
ISSN:2470-9468
DOI:10.1126/sciimmunol.adg0878
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1126/sciimmunol.adg0878
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Author Notes:Etienne Humblin, Isabel Korpas, Jiahua Lu, Dan Filipescu, Verena van der Heide, Simon Goldstein, Abishek Vaidya, Alessandra Soares-Schanoski, Beatrice Casati, Myvizhi E. Selvan, Zeynep H. Gümüş, Andreas Wieland, Mauro Corrado, Leona Cohen-Gould, Emily Bernstein, Dirk Homann, Jerry Chipuk, Alice O. Kamphorst
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Summary:During persistent antigen stimulation, such as in chronic infections and cancer, CD8 T cells differentiate into a hypofunctional programmed death protein 1-positive (PD-1+) exhausted state. Exhausted CD8 T cell responses are maintained by precursors (Tpex) that express the transcription factor T cell factor 1 (TCF-1) and high levels of the costimulatory molecule CD28. Here, we demonstrate that sustained CD28 costimulation is required for maintenance of antiviral T cells during chronic infection. Low-level CD28 engagement preserved mitochondrial fitness and self-renewal of Tpex, whereas stronger CD28 signaling enhanced glycolysis and promoted Tpex differentiation into TCF-1neg exhausted CD8 T cells (Tex). Furthermore, enhanced differentiation by CD28 engagement did not reduce the Tpex pool. Together, these findings demonstrate that continuous CD28 engagement is needed to sustain PD-1+ CD8 T cells and suggest that increasing CD28 signaling promotes Tpex differentiation into more functional effector-like Tex, possibly without compromising long-term responses.
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Gesehen am 06.08.2024
Physical Description:Online Resource
ISSN:2470-9468
DOI:10.1126/sciimmunol.adg0878

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