McManus and Valanparambil et al. showed that nearly identical stem-like (PD-1+TCF-1+TOX+) CD8+ T cells emerged as early as day 5 during chronic and acute LCMV infections. Continuous antigen exposure was critical to preserving their stem-like program, as antigen withdrawal led to a phenotypic shift. Reciprocal transfer experiments revealed that early stem-like CD8+ T cells adopted a central memory-like phenotype upon antigen clearance to adapt to acute infections. In contrast, early stem-like CD8+ T cells from acutely infected mice functioned as resource cells in the setting of chronic infection, and responded effectively to PD-1 blockade.
Contributed by Shishir Pant
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 play a key role in PD-1 directed immunotherapy(1-10). These PD-1+ TCF-1+ TOX+ stem-like CD8+ T cells, also referred to as precursors of exhausted T cells(8,9), have a distinct program that allows them to adapt to chronic antigen stimulation. Using the mouse model of chronic LCMV infection we found 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 infection outcome. Indeed, we found 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 next performed reciprocal adoptive transfer experiments to determine the fate of these early stem-like CD8+ T cells after viral clearance versus persistence. Following transfer of day 5 stem-like CD8+ T cells from chronically infected 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 chronic viral infection. Most importantly, our study shows that the host is prepared a priori to deal with a potential chronic infection.
Author Info: (1) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. (
Author Info: (1) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. (2) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. (3) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. (4) Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. (5) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. (6) Department of Urology, Emory University School of Medicine, Atlanta, GA, USA. (7) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. (8) Department of Pathology, Mass General Brigham, Harvard Medical School, Boston, MA, USA. (9) Department of Otolaryngology, The Ohio State University College of Medicine, Columbus, OH, USA. Pelotonia Institute for Immuno-Oncology, The Ohio State University Comprehensive Cancer Center - The James., Columbus, OH, USA. (10) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. (11) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. (12) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. (13) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. (14) The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA. (15) Department of Urology, Emory University School of Medicine, Atlanta, GA, USA. (16) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. (17) Department of Bioengineering, University of Washington, Seattle, WA, USA. (18) Department of Bioengineering, University of Washington, Seattle, WA, USA. (19) Department of Bioengineering, University of Washington, Seattle, WA, USA. (20) Research Division of Immunology, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA, USA. (21) Division of Immunology, Lowance Center for Human Immunology, Department of Medicine, Emory University, Atlanta, GA, USA. (22) Department of Bioengineering, University of Washington, Seattle, WA, USA. (23) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. Winship Cancer Institute of Emory University, Atlanta, GA, USA. Department of Urology, Emory University School of Medicine, Atlanta, GA, USA. (24) Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA. rahmed@emory.edu. Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA. rahmed@emory.edu. Winship Cancer Institute of Emory University, Atlanta, GA, USA. rahmed@emory.edu.
