A unified atlas of CD8 T cell dysfunctional states in cancer and infection

Mol Cell. 2021 Jun 3;81(11):2477-2493.e10. doi: 10.1016/j.molcel.2021.03.045. Epub 2021 Apr 22.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Disease
  • Atlases as Topic
  • CD8-Positive T-Lymphocytes / classification
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Chromatin / chemistry
  • Chromatin / immunology
  • Chronic Disease
  • Epigenesis, Genetic / immunology*
  • Gene Expression Profiling
  • Gene Regulatory Networks
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Immunity, Cellular*
  • Lymphocyte Activation
  • Lymphocytic Choriomeningitis / genetics*
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic Choriomeningitis / pathology
  • Lymphocytic choriomeningitis virus / immunology
  • Lymphocytic choriomeningitis virus / pathogenicity
  • Neoplasms / genetics*
  • Neoplasms / immunology
  • Neoplasms / pathology
  • Principal Component Analysis
  • Single-Cell Analysis
  • Transcription Factors / classification
  • Transcription Factors / genetics*
  • Transcription Factors / immunology
  • Transcription, Genetic
  • Transposases / genetics
  • Transposases / metabolism


  • Chromatin
  • Transcription Factors
  • Transposases