Developmental Relationships of Four Exhausted CD8+ T Cell Subsets Reveals Underlying Transcriptional and Epigenetic Landscape Control Mechanisms

Immunity. 2020 May 19;52(5):825-841.e8. doi: 10.1016/j.immuni.2020.04.014. Epub 2020 May 11.


CD8+ T cell exhaustion is a major barrier to current anti-cancer immunotherapies. Despite this, the developmental biology of exhausted CD8+ T cells (Tex) remains poorly defined, restraining improvement of strategies aimed at "re-invigorating" Tex cells. Here, we defined a four-cell-stage developmental framework for Tex cells. Two TCF1+ progenitor subsets were identified, one tissue restricted and quiescent and one more blood accessible, that gradually lost TCF1 as it divided and converted to a third intermediate Tex subset. This intermediate subset re-engaged some effector biology and increased upon PD-L1 blockade but ultimately converted into a fourth, terminally exhausted subset. By using transcriptional and epigenetic analyses, we identified the control mechanisms underlying subset transitions and defined a key interplay between TCF1, T-bet, and Tox in the process. These data reveal a four-stage developmental hierarchy for Tex cells and define the molecular, transcriptional, and epigenetic mechanisms that could provide opportunities to improve cancer immunotherapy.

Keywords: CD8; PD-1 blockade; T cell exhaustion lineage; T-bet; TCF1; Tox; cancer immunotherapy; chronic infection; epigenetics; exhaustion.

Publication types

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

MeSH terms

  • Animals
  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / immunology
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cells, Cultured
  • Epigenesis, Genetic / genetics
  • Epigenesis, Genetic / immunology*
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-alpha / immunology
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / immunology
  • Humans
  • Immunotherapy / methods
  • Mice, Inbred C57BL
  • Neoplasms / genetics
  • Neoplasms / immunology*
  • Neoplasms / therapy
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / immunology
  • T-Lymphocyte Subsets / immunology*
  • T-Lymphocyte Subsets / metabolism
  • Transcription, Genetic / genetics
  • Transcription, Genetic / immunology*


  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Hepatocyte Nuclear Factor 1-alpha
  • Hnf1a protein, mouse
  • Homeodomain Proteins
  • Rhox8 protein, mouse
  • T-Box Domain Proteins
  • T-box transcription factor TBX21