An early precursor CD8+ T cell that adapts to acute or chronic viral infection

Daniel T. McManus, Rajesh M. Valanparambil, Christopher B. Medina, Christopher D. Scharer, Donald J. McGuire, Ewelina Sobierajska, Yinghong Hu, Daniel Y. Chang, Andreas Wieland, Judong Lee, Tahseen H. Nasti, Masao Hashimoto, James L. Ross, Nataliya Prokhnevska, Maria A. Cardenas, Amanda L. Gill, Elisa C. Clark, Kathleen Abadie, Arjun J. Kumar, Jonathan Kaye, Byron B. Au-Yeung, Hao Yuan Kueh, Haydn T. Kissick and Rafi Ahmed ()
Additional contact information
Daniel T. McManus: Emory University School of Medicine
Rajesh M. Valanparambil: Emory University School of Medicine
Christopher B. Medina: Emory University School of Medicine
Christopher D. Scharer: Emory University School of Medicine
Donald J. McGuire: Emory University School of Medicine
Ewelina Sobierajska: Emory University School of Medicine
Yinghong Hu: Emory University School of Medicine
Daniel Y. Chang: Harvard Medical School
Andreas Wieland: The Ohio State University College of Medicine
Judong Lee: Emory University School of Medicine
Tahseen H. Nasti: Emory University School of Medicine
Masao Hashimoto: Emory University School of Medicine
James L. Ross: Emory University School of Medicine
Nataliya Prokhnevska: Icahn School of Medicine at Mount Sinai
Maria A. Cardenas: Emory University School of Medicine
Amanda L. Gill: Emory University School of Medicine
Elisa C. Clark: University of Washington
Kathleen Abadie: University of Washington
Arjun J. Kumar: University of Washington
Jonathan Kaye: Cedars-Sinai Medical Center
Byron B. Au-Yeung: Emory University
Hao Yuan Kueh: University of Washington
Haydn T. Kissick: Emory University School of Medicine
Rafi Ahmed: Emory University School of Medicine

Nature, 2025, vol. 640, issue 8059, 772-781

Abstract: Abstract This study examines the origin and differentiation of stem-like CD8+ T cells that are essential for sustained T cell immunity in chronic viral infections and cancer and also have a key role in PD-1 directed immunotherapy1–10. These PD-1+TCF-1+TOX+ stem-like CD8+ T cells (also known as precursors of exhausted T cells8,9) have a distinct program that enables them to adapt to chronic antigen stimulation. Here, using the mouse model of chronic lymphocytic choriomeningitis virus (LCMV) infection, we find that virus-specific stem-like CD8+ T cells are generated early (day 5) during chronic infection, suggesting that this crucial fate commitment occurs irrespective of the infection outcome. Indeed, we find that nearly identical populations of stem-like CD8+ T cells were generated early during acute or chronic LCMV infection, and that antigen was essential for maintaining the stem-like phenotype. We performed reciprocal adoptive transfer experiments to determine the fate of these early stem-like CD8+ T cells after viral clearance versus persistence. After transfer of day 5 stem-like CD8+ T cells from chronically infected mice into acutely infected mice, these cells downregulated canonical markers of the chronic stem-like CD8+ T cells and expressed markers (CD127 and CD62L) associated with central memory CD8+ T cells. Reciprocally, when day 5 stem-like cells from acutely infected mice were transferred into chronically infected mice, these CD8+ T cells functioned like chronic resource cells and responded effectively to PD-1 therapy. These findings highlight the ability of these early PD-1+TCF-1+TOX+ stem-like CD8+ T cells to adapt their differentiation trajectory to either an acute or a chronic viral infection. Importantly, our study shows that the host is prepared a priori to deal with a potential chronic infection.

Date: 2025
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DOI: 10.1038/s41586-024-08562-y

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