We have developed a number of transgenic mice and mice with targeted mutations as tools for understanding the mechanisms (receptor dependent and independent) that shape the immune repertoire. These strains and the phosphocholine (PC) model have been used to define the relationships between antigen recognition and protective, ineffective and detrimental immune responses and to understand the impact that an aging immune repertoire has on immune response. The immune response to PC is important because in mice it has been shown to confer a high degree of protection against infection by Streptococcus pneumoniae (SPn.), a pathogen that poses a significant risk to elderly, very young and immunocompromised individuals. Recently, we have shown that the mouse VH1 gene is essential for immune response to PC and PC-mediated protection against infection by SPn. Furthermore, by examining the associations between the VH1 gene and various light chains in PC-specific B cells we have identified IgL chain structural determinants that may explain differences in the relative affinity/avidity of VH1/VL chain combinations for different PC containing antigens. Analysis of these models should provide insight into the complimentary contribution of interactions between VH and VL genes to protective versus ineffective immune responses to common determinants expressed on different pathogens. We have continued to expand our initial observations on dual isotype expressing B cells. These B cells express receptors that recognize antigens that are both autoreactive and essential for protection against infectious pathogens. We had suggested that coexpression of a second antigen receptor may provide a mechanism termed """"""""receptor dilution"""""""" by which a host can balance the necessity to avoid self reactivity (which could result in holes in the available repertoire) with the evolutionary pressure to provide protection against specific pathogens. This mechanism may be general mechanism for shaping the B cell repertoire. Our current observations in wild type C57BL/6 mice have demonstrated that dual receptor expressing B cells are a part of the normal wild type B cell repertoire. Interestingly, analogous to the VH and VK genes used in the PC-transgenic model, the VH and VK genes expressed by this small population of B cells in wild type C57BL/6 mice have inferred specificities for both autoreactive antigens as well as antigens expressed on pathogens. In addition, we have shown that TdT (terminal deoxynucleotidyl transferase) plays an important role in shaping the immune repertoire. Specifically, we have demonstrated that the generation of the dominant M603id response to immunization with Proteus morganii is dependent upon TdT expression. Subsequently, we have demonstrated that TdT expression affects the size of a population of autoreactive, PtC-specific B1 B cells as well as the expressed VH gene repertoire in this population. Continued examination of the contribution these and other components play in shaping the immune repertoire will further expand our understanding of the mechanisms that distinguish between protective, ineffective and detrimental immune responses.
