Precursors of exhausted T cells are pre-emptively formed in acute infection

Talyn Chu, Ming Wu (), Barbara Hoellbacher, Gustavo P. Almeida, Christine Wurmser, Jacqueline Berner, Lara V. Donhauser, Ann-Katrin Gerullis, Siran Lin, J. Diego Cepeda-Mayorga, Iman I. Kilb, Lukas Bongers, Fabio Toppeta, Philipp Strobl, Ben Youngblood, Anna M. Schulz, Alfred Zippelius, Percy A. Knolle, Matthias Heinig (), Carl-Philipp Hackstein () and Dietmar Zehn ()
Additional contact information
Talyn Chu: Technical University of Munich
Ming Wu: Technical University of Munich
Barbara Hoellbacher: Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt
Gustavo P. Almeida: Technical University of Munich
Christine Wurmser: Technical University of Munich
Jacqueline Berner: Technical University of Munich
Lara V. Donhauser: Technical University of Munich
Ann-Katrin Gerullis: Technical University of Munich
Siran Lin: Technical University of Munich
J. Diego Cepeda-Mayorga: Technical University of Munich
Iman I. Kilb: Technical University of Munich
Lukas Bongers: Technical University of Munich
Fabio Toppeta: Technical University of Munich
Philipp Strobl: Technical University of Munich
Ben Youngblood: St Jude Children’s Research Hospital
Anna M. Schulz: Technical University of Munich
Alfred Zippelius: University Hospital Basel
Percy A. Knolle: Technical University of Munich
Matthias Heinig: Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt
Carl-Philipp Hackstein: Technical University of Munich
Dietmar Zehn: Technical University of Munich

Nature, 2025, vol. 640, issue 8059, 782-792

Abstract: Abstract T cell exhaustion limits effector T cell function in chronic infection and tumours1,2. The development of these hypofunctional T cells and of their precursors was considered to require stimulatory conditions that are met only after persistent exposure to antigen and inflammation. Here we show, however, that similar T cell populations exist in the early phase of acute infections1,2. At that stage, the early developing TCF1+ precursor population exhibits an unexpected diversity; it includes precursors of normal memory T cells, but also cells with phenotypic, gene-expression and epigenetic profiles that resemble those of precursors of exhausted T cells found in chronic infections. We show that high ligand affinity promotes and PD-1 signalling restricts the development of these precursors. Although the exhausted precursors are at first found frequently, they decline without being completely lost in infections that the immune system resolves. We therefore conclude that precursor T cells with at least two distinct phenotypes are pre-emptively generated irrespective of the outcome of an infection.

Date: 2025
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DOI: 10.1038/s41586-024-08451-4

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