The CD40 gene encodes CD40, a transmembrane protein belonging to the tumor necrosis factor receptor (TNFR) superfamily. Primarily expressed on antigen-presenting cells (APCs) such as B lymphocytes, macrophages, and dendritic cells, CD40 is also found on a variety of non-immune cells including endothelial cells, fibroblasts, epithelial cells, and smooth muscle cells, as well as many tumor cells ^[1]. The interaction of CD40 with its ligand, CD40L (CD154), expressed predominantly on activated T helper cells, is a critical costimulatory signal essential for T-dependent humoral and cell-mediated immunity. This interaction triggers downstream signaling pathways, including NF-κB, JNK, and JAK/STAT, leading to B cell activation, proliferation, differentiation, isotype switching, memory B cell development, germinal center formation, and enhanced APC function and cytokine production ^[2]. Dysregulation of CD40 signaling is implicated in the pathogenesis of numerous diseases, including autoimmune disorders like inflammatory bowel disease, type 1 diabetes, multiple sclerosis, and rheumatoid arthritis, as well as cardiovascular diseases such as atherosclerosis, certain neurological conditions including Alzheimer's disease and traumatic brain injury, and various cancers ^[2-4]. Conversely, mutations in CD40 can lead to primary immunodeficiencies like autosomal recessive Hyper IgM syndrome ^[1]. Due to its central role in immune and inflammatory responses, CD40 is a significant target for therapeutic intervention, particularly in cancer immunotherapy and autoimmune diseases.

The B6-hCD40 mouse is a humanized model constructed by replacing the endogenous extracellular domain of the mouse Cd40 with the corresponding extracellular domain from the human CD40 gene. The murine signal peptide and transmembrane-cytoplasmic region were preserved. The B6-hCD40 mice can be used for studies on pathogenesis of cancer and autoimmune diseases, as well as for CD40-targeted drug development.