In the present work we established a new approach to generate fully human mAbs. We immortalized B cells from vaccinated HIS mice by transduction with BCL6 and BCL-XL followed by expansion in presence of IL-21 and CD40L. Antigen-specific B cell clones were obtained that expressed the BCR on their cell surface and secreted antigen-specific antibodies. Similarly to methods based on the immortalization of human memory B cells from individuals that were either vaccinated or exposed to pathogens, our strategy exploits the antibody repertoire of human B cells which is likely to be different from that of B cells of mice expressing human Ig gene segments.