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.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Author information
Authors and Affiliations
Corresponding authors
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.
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.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
DOI: https://doi.org/10.1038/s41586-024-08451-4