Genetic background shapes the naïve IgM B cell receptor repertoire in mice

Abstract

Introduction The B cell receptor (BCR) repertoire is generated through stochastic V(D)J recombination and further shaped by selection processes. Still, the influence of genetic background on the naïve repertoire remains unclear. In this study, we investigated inter-individual and inter-strain variations in the IgM BCR repertoire using naïve mice from three strains: BALB/c, C57BL/6N, and NC/Nga. Methods Splenic IgM-expressing B cells were isolated at the single-cell level, and paired IGHV and IGKV sequences were analyzed. Results Analysis of V gene usage revealed no significant differences in overall diversity among strains. However, analysis using the Jaccard index demonstrated that IGHV repertoires were highly similar within strains but apparently different between strains, whereas IGKV repertoires showed minimal variation. t-SNE and MDS visualizations further supported these findings, with clear clustering by strain observed for IGHV but not for IGKV. The CDR3 nucleotide and amino acid lengths showed no substantial differences among strains, and minimal sharing of CDR3 sequences was observed both inter- and intra-strain, indicating high individual variability. Notably, analysis of IGHV–IGKV pairing revealed that each VH segment was preferentially associated with a specific Vκ segment in a strain-dependent manner. Discussion These results suggest that the naïve BCR repertoire is influenced by genetic background, particularly through biases in heavy-chain gene selection and VH/Vκ pairing. This intrinsic repertoire bias may contribute to strain-specific differences in antigen recognition and susceptibility to some immune-related diseases.