BACH2 enforces the transcriptional and epigenetic programs of stem-like CD8+ T cells

Nat Immunol. 2021 Mar;22(3):370-380. doi: 10.1038/s41590-021-00868-7. Epub 2021 Feb 11.

Abstract

During chronic infection and cancer, a self-renewing CD8+ T cell subset maintains long-term immunity and is critical to the effectiveness of immunotherapy. These stem-like CD8+ T cells diverge from other CD8+ subsets early after chronic viral infection. However, pathways guarding stem-like CD8+ T cells against terminal exhaustion remain unclear. Here, we show that the gene encoding transcriptional repressor BACH2 is transcriptionally and epigenetically active in stem-like CD8+ T cells but not terminally exhausted cells early after infection. BACH2 overexpression enforced stem-like cell fate, whereas BACH2 deficiency impaired stem-like CD8+ T cell differentiation. Single-cell transcriptomic and epigenomic approaches revealed that BACH2 established the transcriptional and epigenetic programs of stem-like CD8+ T cells. In addition, BACH2 suppressed the molecular program driving terminal exhaustion through transcriptional repression and epigenetic silencing. Thus, our study reveals a new pathway that enforces commitment to stem-like CD8+ lineage and prevents an alternative terminally exhausted cell fate.

Publication types

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

MeSH terms

  • Animals
  • Arenaviridae Infections / genetics
  • Arenaviridae Infections / immunology
  • Arenaviridae Infections / metabolism*
  • Arenaviridae Infections / virology
  • Basic-Leucine Zipper Transcription Factors / deficiency
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism*
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism*
  • CD8-Positive T-Lymphocytes / virology
  • Cell Differentiation*
  • Cell Lineage
  • Cells, Cultured
  • Chronic Disease
  • Disease Models, Animal
  • Epigenesis, Genetic*
  • Host-Pathogen Interactions
  • Lymphocytic choriomeningitis virus / immunology
  • Lymphocytic choriomeningitis virus / pathogenicity
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phenotype
  • Precursor Cells, T-Lymphoid / immunology
  • Precursor Cells, T-Lymphoid / metabolism*
  • Precursor Cells, T-Lymphoid / virology
  • Signal Transduction
  • Transcription, Genetic*

Substances

  • Bach2 protein, mouse
  • Basic-Leucine Zipper Transcription Factors