Single-cell RNA-seq reveals TOX as a key regulator of CD8+ T cell persistence in chronic infection

Nat Immunol. 2019 Jul;20(7):890-901. doi: 10.1038/s41590-019-0403-4. Epub 2019 Jun 17.

Abstract

Progenitor-like CD8+ T cells mediate long-term immunity to chronic infection and cancer and respond potently to immune checkpoint blockade. These cells share transcriptional regulators with memory precursor cells, including T cell-specific transcription factor 1 (TCF1), but it is unclear whether they adopt distinct programs to adapt to the immunosuppressive environment. By comparing the single-cell transcriptomes and epigenetic profiles of CD8+ T cells responding to acute and chronic viral infections, we found that progenitor-like CD8+ T cells became distinct from memory precursor cells before the peak of the T cell response. We discovered a coexpression gene module containing Tox that exhibited higher transcriptional activity associated with more abundant active histone marks in progenitor-like cells than memory precursor cells. Moreover, thymocyte selection-associated high mobility group box protein TOX (TOX) promoted the persistence of antiviral CD8+ T cells and was required for the programming of progenitor-like CD8+ T cells. Thus, long-term CD8+ T cell immunity to chronic viral infection requires unique transcriptional and epigenetic programs associated with the transcription factor TOX.

Publication types

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

MeSH terms

  • Animals
  • Biomarkers
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism*
  • Chromatin Immunoprecipitation
  • Epigenesis, Genetic
  • Gene Expression Profiling
  • Gene Expression Regulation*
  • High-Throughput Nucleotide Sequencing
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Host-Pathogen Interactions / genetics
  • Host-Pathogen Interactions / immunology
  • Immunologic Memory
  • Infections / etiology*
  • Infections / metabolism
  • Lymphocytic Choriomeningitis / immunology
  • Lymphocytic Choriomeningitis / virology
  • Lymphocytic choriomeningitis virus / immunology
  • Mice
  • Single-Cell Analysis*
  • Time Factors
  • Transcriptome

Substances

  • Biomarkers
  • Homeodomain Proteins
  • Rhox8 protein, mouse