Daniel, Yost, and Hsiung et al. generated a differentiation atlas of T cell exhaustion in murine chronic viral infection. Analysis revealed that a Tex program is likely initiated in an early effector exhausted (Texeeff) subset, which differentiates towards a progenitor subset (Texprog), followed by an intermediate (Texint) subset. Differentiation then bifurcates towards a late-stage terminal exhaustion (Texterm) phenotype associated with high TCR avidity, a killer cell lectin-like receptor-expressing cytotoxic (TexKLR) phenotype associated with low TCR avidity, or “divergent” clones that acquire both phenotypes. Trajectories were generally shared across tissues. Similar patterns could be observed in human TILs.
Contributed by Lauren Hitchings
ABSTRACT: Chronic antigen exposure during viral infection or cancer promotes an exhausted T cell (Tex) state with reduced effector function. However, whether all antigen-specific T cell clones follow the same Tex differentiation trajectory remains unclear. Here, we generate a single-cell multiomic atlas of T cell exhaustion in murine chronic viral infection that redefines Tex phenotypic diversity, including two late-stage Tex subsets with either a terminal exhaustion (Tex(term)) or a killer cell lectin-like receptor-expressing cytotoxic (Tex(KLR)) phenotype. We use paired single-cell RNA and T cell receptor sequencing to uncover clonal differentiation trajectories of Tex(term)-biased, Tex(KLR)-biased or divergent clones that acquire both phenotypes. We show that high T cell receptor signaling avidity correlates with Tex(term), whereas low avidity correlates with effector-like Tex(KLR) fate. Finally, we identify similar clonal differentiation trajectories in human tumor-infiltrating lymphocytes. These findings reveal clonal heterogeneity in the T cell response to chronic antigen that influences Tex fates and persistence.
Author Info: (1) Department of Pathology, Stanford University, Stanford, CA, USA. Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA. Gladstone-UCSF Institute of Geno
Author Info: (1) Department of Pathology, Stanford University, Stanford, CA, USA. Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (2) Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA. (3) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. (4) Department of Pathology, Stanford University, Stanford, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (5) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. (6) Department of Pathology, Stanford University, Stanford, CA, USA. (7) Department of Pathology, Stanford University, Stanford, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (8) Department of Pathology, Stanford University, Stanford, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (9) Department of Pathology, Stanford University, Stanford, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. (10) Department of Pathology, Stanford University, Stanford, CA, USA. Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA. (11) Department of Pathology, Stanford University, Stanford, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. (12) Department of Pathology, Stanford University, Stanford, CA, USA. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, 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. Parker Institute for Cancer Immunotherapy at 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. Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA. (15) Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA. (16) Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA. (17) Department of Pathology, Stanford University, Stanford, CA, USA. satpathy@stanford.edu. Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA. satpathy@stanford.edu. Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA. satpathy@stanford.edu. Stanford Cancer Institute, Stanford University, Stanford, CA, USA. satpathy@stanford.edu.
