Divergent clonal differentiation trajectories of T cell exhaustion.

Autor: Daniel B; 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., Yost KE; Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA., Hsiung S; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA., Sandor K; Department of Pathology, Stanford University, Stanford, CA, USA.; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA., Xia Y; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA., Qi Y; Department of Pathology, Stanford University, Stanford, CA, USA., Hiam-Galvez KJ; Department of Pathology, Stanford University, Stanford, CA, USA.; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA., Black M; Department of Pathology, Stanford University, Stanford, CA, USA.; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA., J Raposo C; Department of Pathology, Stanford University, Stanford, CA, USA.; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA., Shi Q; Department of Pathology, Stanford University, Stanford, CA, USA.; Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA., Meier SL; 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., Belk JA; Department of Pathology, Stanford University, Stanford, CA, USA.; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA., Giles JR; 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., Wherry EJ; 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., Chang HY; Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.; Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA., Egawa T; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA., Satpathy AT; 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.
Jazyk: angličtina
Zdroj: Nature immunology [Nat Immunol] 2022 Nov; Vol. 23 (11), pp. 1614-1627. Date of Electronic Publication: 2022 Oct 26.
DOI: 10.1038/s41590-022-01337-5
Abstrakt: 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.
(© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)
Databáze: MEDLINE
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