KLF2 controls thymic epithelial cell homeostasis, impacting regulatory T cell development and central tolerance.
T cell development critically 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. Medullary TECs (mTECs), in particular, exhibit remarkable functional heterogeneity driven by complex genetic programs that are essential for establishing 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 cortical and medullary TEC subsets, including several recently identified mimetic TECs. These perturbations imprint sustained thymic function 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, reflecting increased susceptibility to loss of self-tolerance. Collectively, our findings reveal KLF2 as a critical determinant of thymic epithelial homeostasis and immune self-tolerance.