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 have been used to define the relationships between antigen recognition and protective, ineffective or detrimental immune responses in the phosphocholine (PC) model and to examine the impact that the changing immune repertoire with aging has on immune response. The immune response to PC is important because (in mouse models) 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. In PC-specific VH1/IgL chain pairs, we have also identified IgL chain structural determinants that may explain differences in the relative affinity/avidity of VH1/VL chain combinations as well as associated differences in immune response of the B cells expressing the variant receptors. We have continued to expand our initial observations on B cells that express receptors which are both autoreactive and essential for protection against infectious pathogens by proposing that coexpression (""""""""receptor dilution"""""""") may be general mechanism for shaping the B cell repertoire and that coexpression of a second antigen receptor may provide a mechanism by which the 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. Additionally, we have shown that TdT is important in shaping the immune repertoire by demonstrating TdT's essential role in the generation of the dominant M603id response to immunization with Proteus morganii. Continued examination of the contribution these and other components play in shaping the immune repertoire will help our understanding of the distinctions between protective, ineffective and detrimental immune responses
