Giles et al. used paired scRNAseq and scATACseq to study differentiation of gp33-specific CD8+ T cells over time in LCMV models. Within major CD8+ T cell clusters (exhausted (Tex), effector (Teff), and memory), distinct subpopulations diverged epigenetically or, more commonly, transcriptionally, and differed between acute or chronic LCMV infection, including among Tcf7+ cells. In chronic infection, a novel Tex phenotype expressing NK cell-associated genes (e.g., Klr genes) was driven by Zeb2 and represented a later-stage Tex phenotype after PD-1 blockade. Btg1, a stress response gene, was involved in differentiation of activated Teff to Tex cells.
Contributed by Alex Najibi
ABSTRACT: Naïve CD8(+) T cells can differentiate into effector (T(eff)), memory (T(mem)) or exhausted (T(ex)) T cells. These developmental pathways are associated with distinct transcriptional and epigenetic changes that endow cells with different functional capacities and therefore therapeutic potential. The molecular circuitry underlying these developmental trajectories and the extent of heterogeneity within T(eff), T(mem) and T(ex) populations remain poorly understood. Here, we used the lymphocytic choriomeningitis virus model of acute-resolving and chronic infection to address these gaps by applying longitudinal single-cell RNA-sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin sequencing (scATAC-seq) analyses. These analyses uncovered new subsets, including a subpopulation of T(ex) cells expressing natural killer cell-associated genes that is dependent on the transcription factor Zeb2, as well as multiple distinct TCF-1(+) stem/progenitor-like subsets in acute and chronic infection. These data also revealed insights into the reshaping of T(ex) subsets following programmed death 1 (PD-1) pathway blockade and identified a key role for the cell stress regulator, Btg1, in establishing the T(ex) population. Finally, these results highlighted how the same biological circuits such as cytotoxicity or stem/progenitor pathways can be used by CD8(+) T cell subsets with highly divergent underlying chromatin landscapes generated during different infections.
Author Info: (1) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology, Perelman School of Medicine, Uni
Author Info: (1) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (2) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (3) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (4) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (5) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (6) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA. (7) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. Infectious Disease & Vaccines, MRL, Merck & Co. Inc., West Point, PA, USA. (8) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA. (9) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA. (10) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (11) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (12) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (13) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (14) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (15) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. Immunology Graduate Program, Stanford University, Stanford, CA, USA. (16) Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA. (17) Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA. (18) Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. (19) Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA. Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (20) Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania, Philadelphia, PA, USA. wherry@pennmedicine.upenn.edu. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. wherry@pennmedicine.upenn.edu. Parker Institute for Cancer Immunotherapy, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. wherry@pennmedicine.upenn.edu.
