Even when IgG was used as a selection criterion, we were unable to establish antigen-specific IgG + human B cell clones. The reason for this might be that T cell help in this system is suboptimal as indicated by the absence of antigen-specific T cell responses after vaccination (not shown). We also observed that the BCR of the B cell clones had a close to germ-line sequence, suggesting that also the induction of somatic hyper-mutation is sub-optimal in HIS mice. In our hands the great majority of the vaccinated HIS mice showed a defective formation of germinal centers [14, 16] , which further explains the absence of antigenspecific Ig-class switched B cells. So far, humanized mouse models based on the transplantation of human HSC only -i.e. without additional human tissues -share these limitations, and immunization strategies result in the limited generation of class-switched antigen-specific B cell responses [14, 31, 32] . Similar patterns are observed in human HSC-transplanted immunodeficient mice infected with lymphotropic pathogens, such as HIV [33] or EBV [34] , although Dengue virus infection in HIS mice was reported to induce an IgG response in a majority of the responder animals [35] . It is not clear why IgG antigen-specific responses are limited while serum IgG can accumulate efficiently, considering the low frequency of IgG + B cells in HIS mice. It remains to be determined whether this apparent discrepancy might be explained by the conjunction of particularly effective IgG production on a cell basis by IgG + B cells (which might occur in a T cell independent manner, such as in the case of the IgG3 subclass), long-term stability of human IgG in the HIS mouse serum as compared to human IgM, and/or defective survival of IgG + B cells under specific conditions (e.g. after antigen-specific triggering of the BCR).