KLF2 controls thymic epithelial cell homeostasis, impacting regulatory T cell development and immune tolerance.

T cell development depends on specialized thymic microenvironments formed by cortical (c) and medullary (m) thymic epithelial cells (TECs), which arise from a common epithelial progenitor. However, the molecular mechanisms that govern TEC differentiation and function remain poorly understood. Particularly, mTECs display remarkable functional heterogeneity driven by complex genetic programs essential for central tolerance. Here, we investigated the role of the transcription factor KLF2 in TEC biology. TEC-specific deletion of KLF2 (KLF2 cKO) in mice impairs mTEC maintenance and selectively remodels transcriptional programs across cTEC and mTEC subsets, including several recently identified mimetic TECs. These perturbations imprint sustained thymic dysfunction and restrict regulatory T cell differentiation and function. Furthermore, KLF2 cKO mice show increased lymphocytic infiltration in peripheral tissues in aged and autoimmune-prone models, suggesting an increased susceptibility to the breakdown of immunological self-tolerance. Our findings highlight KLF2 as a critical regulator of TEC homeostasis and the prevention of autoimmunity.