TET Enzymes in the Immune System: From DNA Demethylation to Immunotherapy, Inflammation, and Cancer

Annu Rev Immunol. 2024 Jun;42(1):455-488. doi: 10.1146/annurev-immunol-080223-044610. Epub 2024 Jun 14.

Abstract

Ten-eleven translocation (TET) proteins are iron-dependent and α-ketoglutarate-dependent dioxygenases that sequentially oxidize the methyl group of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC). All three epigenetic modifications are intermediates in DNA demethylation. TET proteins are recruited by transcription factors and by RNA polymerase II to modify 5mC at enhancers and gene bodies, thereby regulating gene expression during development, cell lineage specification, and cell activation. It is not yet clear, however, how the established biochemical activities of TET enzymes in oxidizing 5mC and mediating DNA demethylation relate to the known association of TET deficiency with inflammation, clonal hematopoiesis, and cancer. There are hints that the ability of TET deficiency to promote cell proliferation in a signal-dependent manner may be harnessed for cancer immunotherapy. In this review, we draw upon recent findings in cells of the immune system to illustrate established as well as emerging ideas of how TET proteins influence cellular function.

Keywords: DNA methylation; TET2 mutations; cancer; cancer immunotherapy; dioxygenases; hematopoietic malignancies; oxidized methylcytosines.

Publication types

  • Review

MeSH terms

  • Animals
  • DNA Demethylation*
  • DNA Methylation
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Dioxygenases* / metabolism
  • Epigenesis, Genetic
  • Humans
  • Immune System / immunology
  • Immune System / metabolism
  • Immunotherapy* / methods
  • Inflammation* / immunology
  • Inflammation* / metabolism
  • Mixed Function Oxygenases / genetics
  • Mixed Function Oxygenases / metabolism
  • Neoplasms* / etiology
  • Neoplasms* / immunology
  • Neoplasms* / metabolism
  • Neoplasms* / therapy
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism

Substances

  • Dioxygenases
  • Proto-Oncogene Proteins
  • DNA-Binding Proteins
  • Mixed Function Oxygenases