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

• 成果类型: Article
• 署名作者: Mcmanus, Daniel T.; Valanparambil, Rajesh M.; Medina, Christopher B.; Scharer, Christopher D.; Mcguire, Donald J.; Sobierajska, Ewelina; Hu, Yinghong; Chang, Daniel Y.; Wieland, Andreas; Lee, Judong; Nasti, Tahseen H.; Hashimoto, Masao; Ross, James L.; Prokhnevska, Nataliya; Cardenas, Maria A.; Gill, Amanda L.; Clark, Elisa C.; Abadie, Kathleen; Kumar, Arjun J.; Kaye, Jonathan; Au-Yeung, Byron B.; Kueh, Hao Yuan; Kissick, Haydn T.; Ahmed, Rafi
• 署名单位: Emory University; Emory University; Emory University; Harvard University; Harvard Medical School; Adventist Health Services; AdventHealth; Mass General Brigham; University System of Ohio; Ohio State University; University System of Ohio; Ohio State University; Icahn School of Medicine at Mount Sinai; University of Washington; University of Washington Seattle; Cedars Sinai Medical Center; Emory University; Emory University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-1556
• DOI: 10.1038/s41586-024-08562-y
• 发表日期: 2025-04-17
• 关键词: follicular helper; expression; differentiation; persistence; metabolism; program

摘要

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, 2, 3, 4, 5, 6, 7, 8, 9-10. 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.