Targeting the HLA-B40.1 Axis: Biological Roles and Therapeutic Strategies 

• Gene Information: The HLA-B gene, located on chromosome 6p21.3 within the Major Histocompatibility Complex (MHC) locus, encodes the highly polymorphic HLA-B40.1 alpha chain, a crucial component of the human leukocyte antigen class I system. 
• Protein Expression: HLA-B40.1 is a codominantly and ubiquitously expressed cell-surface glycoprotein found on almost all nucleated cells, where it forms a heterotrimer with β2-microglobulin and an 8-to-10 amino acid endogenous peptide. 
• Signaling Pathway: It presents intracellular antigenic peptides directly to CD8+ T-cell receptors (TCRs), triggering a downstream signaling cascade that drives cytotoxic cell lysis. 
• Therapeutic Inhibition: Rather than blocking its function, therapies exploit HLA-B40.1 by developing cancer vaccines, TCR-like antibodies and T-cell engagers that selectively target the specific tumor-peptide/HLA-B40.1 complex.

HLA-B40.1

•  The B2M gene (Exon1 to Exon3) of mouse were replaced by the sequence encompassing the human B2M CDS and HLA-B*4001 gene that included leader sequence, α1 and α2 domains ligated to a fragment of the murine H-2D^b gene containing the α3, transmembrane and cytoplasmic domains in B-HLA-B40.1 mice.

Strain specific B2M and HLA-B40.1 expression analysis in wild-type C57BL/6JNifdc mice and homozygous humanized B-HLA-B40.1 mice by flow cytometry. Splenocytes (A) and blood (B) were collected from wild-type C57BL/6JNifdc mice (+/+) and homozygous B-HLA-B40.1 mice (H/H), respectively, and analyzed by flow cytometry with species-specific anti-HLA-B40.1 (Biolegend, 311406), anti-H-2Db (Biolegend, 111513), anti-hB2M (Biolegend, 395712), and anti-mB2M (BD Biosciences, 744802) antibody.