Disruption of Notch Signaling by KGF Induces a Developmental Pause in Thymocytes

Ruifeng Teng^1*Francis A. Flomerfelt¹Ping Xue¹Constance Tom Noguchi²Ronald E Gress¹Naomi Taylor^1*

• ¹National Cancer Institute Center for Cancer Research, Bethesda, United States
• ²National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, United States

Keratinocyte growth factor (KGF) has been proposed as a therapeutic adjuvant to enhance T cell immune reconstitution, particularly following stem cell transplantation. Here, we demonstrate that the long-term KGF-induced increase in thymic cellularity and thymocyte differentiation is preceded by a transient developmental block prior to the -selection checkpoint, observed as early as day 2 following KGF treatment. This early block is characterized by an increased expansion of uncommitted thymocytes and is driven by KGF-induced alterations in both cortical and medullary thymic epithelial cells (TECs). KGF suppresses Wnt/-catenin signaling by downregulating distinct Wnt ligands in cTECs and mTECs, leading to reduced expression of Foxn1, a master regulator of TEC differentiation. Consequently, expression of Foxn1-dependent genes, including Dll4, a key Notch ligand required for early thymocyte development, is diminished. These findings reveal a novel mechanism of KGF action: an initial disruption of TEC-mediated signaling that transiently impairs early thymocyte differentiation, followed by enhanced proliferation and long-term thymic recovery.