Canonical WNT pathway utilizes LEF1 to coordinate innate immune memory 2335059

Abstract Introduction Wnt signaling is a fundamental and evolutionarily conserved pathway that governs cell fate, proliferation, and tissue homeostasis. While canonical Wnt/β-catenin signaling has been extensively characterized in stem and stromal cells, its function in lymphocytes remains context dependent and poorly understood. Natural killer (NK) cells provide a powerful system to interrogate this pathway, as they bridge innate and adaptive immunity and undergo antigen-specific clonal expansion and memory formation during antiviral responses such as cytomegalovirus (CMV) infection. Given the capacity of canonical Wnt/β-Catenin signaling to orchestrate core cellular processes, defining how NK cells access and interpret this conserved pathway to shape the transcriptional architecture of antiviral immunity is of particular interest. Methods We used a well-established model of mouse CMV (MCMV) infection, in which Ly49H+ NK cells recognize the viral glycoprotein m157 on infected targets. Molecular, genomic, and epigenomic approaches were applied to dissect how NK cells utilize Wnt signaling during viral infection. Results We identify a cytokine-independent mechanism of NK cell expansion mediated by canonical Wnt signaling. We found that NK cells uniquely express the Wnt ligand receptor Frizzled-5 (Fzd5), which is essential for regulating β-catenin-dependent canonical Wnt signaling. During MCMV, we demonstrate that the Wnt-Fzd5 signaling pathway requires β-catenin as a co-factor and LEF1 as a downstream transcription factor to activate key regulators of cell cycle entry and proliferation. Conclusion These findings establish Fzd5-mediated canonical Wnt signaling and LEF1 activity as critical drivers of the adaptive NK cell response during viral infection, offering new insights into the regulation of innate immunity. Funding Source T32 AI134632-05; F31AI178958 Topic Categories Innate Immune Responses and Host Defense: Molecular Mechanisms (INM)