Pritykin and Veeken et al. analyzed chromatin accessibility (ATACseq) and gene expression (RNAseq) bulk and single-cell datasets to generate a unified atlas of CD8+ T cell chromatin and expression states, and defined a universal program of progression to terminal dysfunction. In chronic infection and across tumor models, dysfunctional T cells were epigenetically and transcriptionally similar, and T cell state analysis suggested early bifurcation of functional and dysfunctional T cell activation states. Allele-specific analysis revealed state-specific transcription factor expression and TCF1+ progenitor cell populations with similar transcriptional profiles in acute and chronic infection.
Contributed by Shishir Pant
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.
Author Info: (1) Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: pritykin@cbio.mskcc.org. (2) Howard Hughes Medic
Author Info: (1) Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: pritykin@cbio.mskcc.org. (2) Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute, and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (3) Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Tri-Institutional Training Program in Computational Biology and Medicine, New York, NY 10065, USA. (4) Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute, and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (5) Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Tri-Institutional Training Program in Computational Biology and Medicine, New York, NY 10065, USA. (6) Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (7) Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (8) Howard Hughes Medical Institute and Immunology Program, Sloan Kettering Institute, and Ludwig Center at Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. (9) Computational and Systems Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: cleslie@cbio.mskcc.org.
