Transcription factors FOXN1 and intrathymic cytokines contribute to dysfunction of TECs during lipopolysaccharide-induced thymic atrophy.

Sepsis is a major cause of mortality in neonates, yet understanding of sepsis-associated immune dysregulation in early life remains limited. Sepsis-induced thymus atrophy results in disruption of T cell development, accompanied by the dysfunction of thymic epithelial cells (TECs). Here, we sought to identify molecular mechanisms underlying TECs dysfunction while induced sepsis in neonatal mice and immortalized TECs cell line (iTECs) via lipopolysaccharide (LPS) treatment. We identified that LPS induced a reduction in thymocytes number starting at the double-negative stage of thymocyte development and significantly reduced numbers of naïve T cells and recent thymic emigrants (RTEs). Further we confirmed the alterations of intrathymic cytokines influencing T cell development and functionality through the FOXN1 signaling pathway upon exposure to LPS ex vivo and in vivo. LPS treatment decreased the number of cortical TECs (cTECs) and medullary TECs (mTECs) by enhancing the apoptosis of cTECs and decreasing the proliferation of mTECs. These findings provide valuable insights for further study on the innate and specific immunity in response to neonatal sepsis.