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

Yuri Pritykin, Joris van der Veeken, Allison R. Pine, Yi Zhong, Merve Sahin, Linas Mazutis, Dana Pe'er, Alexander Y. Rudensky, Christina S. Leslie

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2477-2493.e10
JournalMolecular Cell
Volume81
Issue number11
DOIs
StatePublished - Jun 3 2021
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Cell Biology

Keywords

  • adoptive transfer
  • ATAC-seq
  • computational integration
  • CUT&RUN
  • RNA-seq
  • single cell
  • T cell dysfunction
  • T cell exhaustion
  • TCF1+ progenitor
  • transcription factors

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