HUMAN MAJOR HISTOCOMPATIBILITY COMPLEX CLASS II-RESTRICTED T-CELL RESPONSES IN TRANSGENIC MICE

Transgenic mice expressing human major histocompatibility complex (MHC ) class II molecules would provide a valuable model system for studyin g human immunology. However, attempts to obtain human class II-restric ted T cell responses in such transgenic mice have had only limited suc cess, possibly due to an inability of mouse CD4 to interact efficientl y with human MHC class II molecules. To circumvent this problem, we co nstructed recombinant MHC class II genes in which the peptide-binding domain was derived from human DR sequences whereas the CD4-binding dom ain was derived from mouse I-E sequences. Purified chimeric human/mous e MHC class II molecules were capable of specifically binding DR-restr icted peptides. Human B cell transformants that expressed these chimer ic MHC class II molecules could present peptide antigens to human T ce ll clones. Expression of these chimeric class II molecules in transgen ic mice led to the intrathymic deletion of T cells expressing superant igen-reactive VP gene segments, indicating that the chimeric class II molecules could influence the selection of the mouse T cell repertoire . These transgenic mice were fully capable of mounting human DR-restri cted immune responses after challenge with peptide or whole protein an tigens. Thus, the chimeric class II molecules can serve as functional antigen presentation molecules in vivo. In addition, transgenic mice e xpressing chimeric class II molecules could be used to generate antige n-specific mouse T cell hybridomas that were capable of interacting wi th human antigen-presenting cells.