@article{9fbcc4ae30814c15aee86704737860c0,
title = "Divergent clonal differentiation trajectories of T cell exhaustion",
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 (Texterm) or a killer cell lectin-like receptor-expressing cytotoxic (TexKLR) phenotype. We use paired single-cell RNA and T cell receptor sequencing to uncover clonal differentiation trajectories of Texterm-biased, TexKLR-biased or divergent clones that acquire both phenotypes. We show that high T cell receptor signaling avidity correlates with Texterm, whereas low avidity correlates with effector-like TexKLR 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 = "Bence Daniel and Yost, {Kathryn E.} and Sunnie Hsiung and Katalin Sandor and Yu Xia and Yanyan Qi and Hiam-Galvez, {Kamir J.} and Mollie Black and {J. Raposo}, Colin and Quanming Shi and Meier, {Stefanie L.} and Belk, {Julia A.} and Giles, {Josephine R.} and Wherry, {E. John} and Chang, {Howard Y.} and Takeshi Egawa and Satpathy, {Ansuman T.}",
note = "Funding Information: A.T.S. is a founder of Immunai and Cartography Biosciences and receives research funding from Allogene Therapeutics and Merck Research Laboratories. H.Y.C. is a cofounder of Accent Therapeutics, Boundless Bio and Cartography Biosciences and an advisor to 10x Genomics, Arsenal Biosciences and Spring Discovery. K.E.Y. is a consultant for Cartography Biosciences. J.A.B. is a consultant for Immunai. E.J.W. is an advisor for Danger Bio, Marengo, Janssen, NewLimit Inc., Pluto Immunotherapeutics, Related Sciences, Rubius Therapeutics, Synthekine and Surface Oncology. E.J.W. is a founder of Surface Oncology, Danger Bio, and Arsenal Biosciences. The remaining authors declare no competing interests. Funding Information: We thank the members of the Satpathy, Egawa and Chang laboratories for stimulating discussions; K. Murphy, Washington University, for providing the NFAT-GFP reporter cells; and C.-S. Hsieh, Washington University, for providing the MSCV-based retroviral plasmid MigCaRCh. This work was supported by the National Institutes of Health (NIH) K08CA230188 (A.T.S.), U01CA260852 (A.T.S.), RM1-HG007735 (H.Y.C.), R01AI130152 (T.E.), R21AI161040 (T.E.), a Career Award for Medical Scientists from the Burroughs Wellcome Fund (A.T.S.), a Technology Impact Award and a Lloyd J. Old STAR Award from the Cancer Research Institute (A.T.S.), an ASH Scholar Award from the American Society of Hematology (A.T.S.), the Parker Institute for Cancer Immunotherapy (E.J.W., H.Y.C. and A.T.S.), a Pew-Stewart Scholars for Cancer Research Award (A.T.S.), a Baxter Foundation Faculty Scholar Award, a Leukemia and Lymphoma Society Scholar Award (T.E.) and the Scleroderma Research Foundation (H.Y.C.). H.Y.C. is an investigator of the Howard Hughes Medical Institute. K.E.Y. was supported by the National Science Foundation Graduate Research Fellowship Program (NSF DGE-1656518) and a Stanford Graduate Fellowship and a NCI Predoctoral to Postdoctoral Fellow Transition Award (NIH F99CA253729). K.H.G. was supported by a Stanford School of Medicine Propel Postdoctoral Scholarship. J.A.B was supported by a Stanford Graduate Fellowship and a National Science Foundation Graduate Research Fellowship under grant number DGE-1656518. C.J.R. was funded by an NIH training grant through the Stanford Immunology Program (5T32AI007290-38). S.H. was supported by an NIH training grant (T32CA009547). J.R.G. was supported by a Cancer Research Institute-Mark Foundation Fellowship and T32CA009140. M.B. was supported by the Stanford Innovative Medicines Accelerator (IMA). The sequencing data were generated with instrumentation purchased with NIH funds: S10OD018220 and 1S10OD021763. Funding Information: We thank the members of the Satpathy, Egawa and Chang laboratories for stimulating discussions; K. Murphy, Washington University, for providing the NFAT-GFP reporter cells; and C.-S. Hsieh, Washington University, for providing the MSCV-based retroviral plasmid MigCaRCh. This work was supported by the National Institutes of Health (NIH) K08CA230188 (A.T.S.), U01CA260852 (A.T.S.), RM1-HG007735 (H.Y.C.), R01AI130152 (T.E.), R21AI161040 (T.E.), a Career Award for Medical Scientists from the Burroughs Wellcome Fund (A.T.S.), a Technology Impact Award and a Lloyd J. Old STAR Award from the Cancer Research Institute (A.T.S.), an ASH Scholar Award from the American Society of Hematology (A.T.S.), the Parker Institute for Cancer Immunotherapy (E.J.W., H.Y.C. and A.T.S.), a Pew-Stewart Scholars for Cancer Research Award (A.T.S.), a Baxter Foundation Faculty Scholar Award, a Leukemia and Lymphoma Society Scholar Award (T.E.) and the Scleroderma Research Foundation (H.Y.C.). H.Y.C. is an investigator of the Howard Hughes Medical Institute. K.E.Y. was supported by the National Science Foundation Graduate Research Fellowship Program (NSF DGE-1656518) and a Stanford Graduate Fellowship and a NCI Predoctoral to Postdoctoral Fellow Transition Award (NIH F99CA253729). K.H.G. was supported by a Stanford School of Medicine Propel Postdoctoral Scholarship. J.A.B was supported by a Stanford Graduate Fellowship and a National Science Foundation Graduate Research Fellowship under grant number DGE-1656518. C.J.R. was funded by an NIH training grant through the Stanford Immunology Program (5T32AI007290-38). S.H. was supported by an NIH training grant (T32CA009547). J.R.G. was supported by a Cancer Research Institute-Mark Foundation Fellowship and T32CA009140. M.B. was supported by the Stanford Innovative Medicines Accelerator (IMA). The sequencing data were generated with instrumentation purchased with NIH funds: S10OD018220 and 1S10OD021763. Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2022",
month = nov,
doi = "10.1038/s41590-022-01337-5",
language = "English",
volume = "23",
pages = "1614--1627",
journal = "Nature immunology",
issn = "1529-2908",
number = "11",
}