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Precursors of exhausted T cells are preemptively formed in acute infection

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Abstract

T cell exhaustion limits effector T cell function in chronic infection and tumors1,2. The development of these hypofunctional T cells and of their precursors was considered to require stimulatory conditions met only upon persisting exposure to antigen and inflammation. In sharp contrast, we found similar T cell populations in the early phase of acute infections1,2. At that stage early developing TCF1+ precursor population shows an unexpected diversity, which includes precursors of normal memory T cells but also cells with a phenotype, gene-expression, and epigenetic profile that resembles precursors of exhausted T cells found in chronic infections. We demonstrate that high ligand affinity promotes, and PD-1 signaling restricts the development of these precursors. While these exhausted precursors are initially frequently found, they decline without being completely lost in infections the immune system resolves. We therefore concluded that precursor T cells with at least two distinct phenotypes are preemptively generated irrespectively of the outcome of the infection.

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Correspondence to Ming Wu, Matthias Heinig, Carl-Philipp Hackstein or Dietmar Zehn.

Supplementary information

Supplementary Methods

scRNASeq analysis. A detailed overview about the different pipelines used to analyze the separate sc-RNA-Seq experiments conducted for this study. We provide information of the platform, language version and an in depth description about the different processing steps up to the clustering of single cells.

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Supplementary Figure 1

Graphical summary. The image provides a graphical illustration of the main finding presented in our manuscript and summarizes the conceptual change we proposed for the development of stem-like progenitors in infections.

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Chu, T., Wu, M., Hoellbacher, B. et al. Precursors of exhausted T cells are preemptively formed in acute infection. Nature (2025). https://doi.org/10.1038/s41586-024-08451-4

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  • DOI: https://doi.org/10.1038/s41586-024-08451-4

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