@article{f219d5b7f2f84677a6fbe5163728a7ae,
title = "A unified atlas of CD8 T cell dysfunctional states in cancer and infection",
abstract = "CD8 T cells play an essential role in defense against viral and bacterial infections and in tumor immunity. Deciphering T cell loss of functionality is complicated by the conspicuous heterogeneity of CD8 T cell states described across experimental and clinical settings. By carrying out a unified analysis of over 300 assay for transposase-accessible chromatin sequencing (ATAC-seq) and RNA sequencing (RNA-seq) experiments from 12 studies of CD8 T cells in cancer and infection, we defined a shared differentiation trajectory toward dysfunction and its underlying transcriptional drivers and revealed a universal early bifurcation of functional and dysfunctional T cell states across models. Experimental dissection of acute and chronic viral infection using single-cell ATAC (scATAC)-seq and allele-specific single-cell RNA (scRNA)-seq identified state-specific drivers and captured the emergence of similar TCF1+ progenitor-like populations at an early branch point, at which functional and dysfunctional T cells diverge. Our atlas of CD8 T cell states will facilitate mechanistic studies of T cell immunity and translational efforts.",
keywords = "ATAC-seq, CUT&RUN, RNA-seq, T cell dysfunction, T cell exhaustion, TCF1+ progenitor, adoptive transfer, computational integration, single cell, transcription factors",
author = "Yuri Pritykin and {van der Veeken}, Joris and Pine, {Allison R.} and Yi Zhong and Merve Sahin and Linas Mazutis and Dana Pe'er and Rudensky, {Alexander Y.} and Leslie, {Christina S.}",
note = "Funding Information: This study was supported by NIH grants U54 CA209975 and R01AI034206, the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center, the Ludwig Center at Memorial Sloan Kettering Cancer Center, the Parker Institute for Cancer Immunotherapy, AACR-Bristol-Myers Squibb Immuno-oncology Research Fellowship (19-40-15-PRIT), and MSK-PICI-Cycle for Survival Fund (to Y.P.). A.Y.R. is an investigator with the Howard Hughes Medical Institute. We thank the NIH tetramer core for providing critical reagents. We acknowledge the use of the MSKCC Integrated Genomics Operation Core, funded by the NIH/NCI Cancer Center Support Grant (P30 CA008748), Cycle for Survival, and the Marie-Josee and Henry R. Kravis Center for Molecular Oncology. We thank Lauren Fairchild for useful discussions and preliminary data analysis; Roshan Sharma and Manu Setty for advice on scRNA-seq analysis; and members of the Leslie, Rudensky, and Pe'er labs for discussion and suggestions. Conceptualization, Y.P. J.v.d.V. A.Y.R. and C.S.L.; methodology, Y.P. J.v.d.V. A.R.P. Y.Z. M.S. L.M. D.P. A.Y.R. and C.S.L.; software, Y.P. A.R.P. Y.Z. M.S. and C.S.L.; formal analysis, Y.P. A.R.P. and C.S.L.; investigation, Y.P. J.v.d.V. A.R.P. Y.Z. M.S. L.M. D.P. A.Y.R. and C.S.L.; writing – original draft, Y.P. and C.S.L.; writing – review & editing, Y.P. J.v.d.V. A.Y.R. and C.S.L.; supervision, Y.P. J.v.d.V. A.Y.R. and C.S.L.; funding acquisition, Y.P. D.P. A.Y.R. and C.S.L. A.Y.R. is an SAB member; has equity in Sonoma Biotherapeutics, RAPT Therapeutics, Surface Oncology, and Vedanta Biosciences; and is a co-inventor or has IP licensed to Takeda that is unrelated to the content of this study. Funding Information: This study was supported by NIH grants U54 CA209975 and R01AI034206 , the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center , the Ludwig Center at Memorial Sloan Kettering Cancer Center, the Parker Institute for Cancer Immunotherapy , AACR-Bristol-Myers Squibb Immuno-oncology Research Fellowship ( 19-40-15-PRIT ), and MSK-PICI-Cycle for Survival Fund (to Y.P.). A.Y.R. is an investigator with the Howard Hughes Medical Institute . We thank the NIH tetramer core for providing critical reagents. We acknowledge the use of the MSKCC Integrated Genomics Operation Core, funded by the NIH/ NCI Cancer Center Support Grant ( P30 CA008748 ), Cycle for Survival , and the Marie-Josee and Henry R. Kravis Center for Molecular Oncology . We thank Lauren Fairchild for useful discussions and preliminary data analysis; Roshan Sharma and Manu Setty for advice on scRNA-seq analysis; and members of the Leslie, Rudensky, and Pe{\textquoteright}er labs for discussion and suggestions. Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",
year = "2021",
month = jun,
day = "3",
doi = "10.1016/j.molcel.2021.03.045",
language = "English (US)",
volume = "81",
pages = "2477--2493.e10",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "11",
}