The TET2 protein is an epigenetic enzyme that catalyzes the oxidation of 5-methylcytosine to 5-hydroxymethylcytosine, a key step in the DNA demethylation process. Loss-of-function mutations in TET2 are frequently found in various immune disorders, notably myeloid and lymphoid hematological malignancies. However, TET2 alteration alone is not sufficient to cause disease, and the diversity of associated clinical presentations raises the question of the precise role of this mutation depending on the type of immune cell involved. Mastocytosis, a rare immune disorder, illustrates this complexity: 20 to 30% of patients carry a TET2 mutation, but fewer than 1% develop mast cell leukemia, suggesting that the role of TET2 established in leukemias does not apply as such in this immune context.
To clarify this point, the authors worked on primary murine mast cells. They first show that Tet2 expression is induced by both acute and chronic activation signals. In TET2-deficient mast cells, chronic activation mediated by the oncogenic KITD816V allele—characteristic of mastocytosis—selects for a distinct epigenetic signature marked by hypermethylated DNA regions at immune response genes. Analysis of H3K27ac histone marks and transcription factor binding reveals a more open, or "primed," chromatin in the vicinity of these immune genes, a configuration that coincides with an increase in pathological inflammatory signals. Methodologically, the team combined genome-wide methylation sequencing (RRBS), chromatin immunoprecipitation (ChIP-Seq), Cut&Run, and transcriptomic analyses (RNA-Seq) in order to link methylation status, chromatin accessibility, and gene expression.
The hypermethylated regions are associated with a subset of immune genes that are direct targets of TET2 and are repressed in its absence. This repression translates into immune tolerance to acute stimulation: TET2-deficient cells respond less to activation signals. The authors establish the reversible and enzymatic-activity-dependent nature of this phenomenon, since the tolerance can be lifted by vitamin C treatment—a cofactor that promotes the activity of TET enzymes—or, conversely, reproduced in normal cells through the use of a TET inhibitor.
Taken together, these data support a model in which TET2 plays a direct role in preventing the establishment of immune tolerance within chronically activated mast cells. The authors thus propose TET2 as a target for reprogramming the innate immune response toward innovative therapies.