TET2 in epigenetic control of immune cells: Implications for inflammatory responses and age-related pathologies

Ten-eleven translocation 2 (TET2) is an epigenetic modifier whose canonical activity leads to the removal of cytosine methylation in the genome, which in essence results in the activation of gene expression. This function is particularly well described in the context of hematopoiesis and its alterations that lead to leukemia. However, in recent years, it has become evident that the noncanonical functions of TET2 also play a vital role in its activity. Rather than depending on its catalytic activity, these functions arise from TET2 interactions with other epigenetic modifiers. This review summarizes the structure, regulation, and functions of TET2 in immune cells. We describe how TET2 controls gene expression at both the DNA and RNA levels. In addition, we discuss the role of TET2 in hematopoietic stem cell fate and in clonal hematopoiesis of indeterminate potential. Finally, we highlight the impact of TET2 mutations on age-related inflammatory diseases, including cardiovascular and neurodegenerative disorders. Collectively, available evidence positions TET2 as a key integrator of epigenetic state and immune signaling, with context-dependent effects on inflammation and tissue homeostasis, and underscores the therapeutic potential of targeting TET2-dependent pathways in clonal hematopoiesis and inflammatory diseases.