Unraveling the molecular evolution and immune functions of Lr-CD40 in Lethenteron reissneri

This study provides the first comprehensive molecular evolutionary and functional characterization of a CD40 ortholog (Lr-CD40) in the Lethenteron reissneri. Utilizing an integrated methodology combining phylogenetic analysis, targeted gene silencing, RNA-seq, protein-level interrogation, and immunological assays, we systematically characterize the evolutionary trajectory, tissue-specific expression, immune response dynamics, and distinct mechanistic function of Lr-CD40 within the TNF receptor signaling pathway. Our results demonstrate that Lr-CD40 orchestrates spatiotemporally precise immunomodulation. This regulation is mediated through distinct mechanisms, including bidirectional immunoregulation via positive feedback loops and temporally compartmentalized activation of immune effectors. Furthermore, pronounced tissue-specific localization within the gill mucosa underpins its specialized role in regional immune surveillance. These results position Lr-CD40 as a potentially central regulatory hub within the lamprey immune system, bridging innate and adaptive immunity while coordinating a critical balance between immune defense and developmental processes. Collectively, this work not only provides novel models and conceptual frameworks for mammalian immunology research but also significantly advances our understanding of the origin and evolution of the vertebrate immune system.