In conclusion, our results show using two standard vaccine antigens the general applicability of an innovative B cell immortalization method in combination with the HIS mouse model to generate human mAbs. Similarly to methods based on the immortalization of human memory B cells from vaccinated or convalescent individuals [9] , our approach exploits the broad antibody repertoire of human B cells, overcoming the potential limitations of conventional humanized murine mAbs such as laboriousness or impaired biological properties, synthetic antibody libraries that require a known target antigen, and transgenic mice bearing the human Ig locus that have limited B cell repertoires. In addition, our method enables to exploit experimental infection models and immunization regimes that would be unethical or untenable in humans. Considering the upcoming advances in HIS mice models [37] , this new approach will provide a powerful tool to generate human mAbs for either diagnostic or therapeutic purposes. Figure S1 IgG/IgA B cell repertoire in naïve HIS mice. Similarly to Figure 1E , the naive IgG (A) and IgA (B) B cell repertoires of HIS (BALB-Rag/c) mice were evaluated on splenocytes by performing a BCR immunoscope for each V H family. The profiles obtained with control human PBMC are also shown. Found at: doi:10.1371/journal.pone.0013137.s001 (1.61 MB TIF) Figure 3 . Limited dilutions of B cells transduced with BCL-6 and BCL-XL were performed with 6.4 and 0.64 cells/well. After sub-cloning of the positive wells, we generated 15 IgM + anti-HBsAg mAbs, of which 13 are unique (as determined by Ig-V H sequence, see Table S3 ), and 18 IgM + anti-TT mAbs, of which 5 are unique (see Table S4 ). In the case of HBsAg vaccination, the number of screened B cells was ((192*6.4)+(96*0.64))*3 = 3870, which eventually suggests that the frequency of HBsAg-specific B cells is at least 1/350 B cells. Found at: doi:10.1371/journal.pone.0013137.s003 (0.13 MB DOC)