Transgenic mice expressing human major histocompatibility complex (MHC) class II molecules would provide a valuable model system for studying human immunology. However, attempts to obtain human class II-restricted T cell responses in such transgenic mice have had only limited success, possibly due to an inability of mouse CD4 to interact efficiently with human MHC class II molecules. To circumvent this problem, we constructed recombinant MHC class II genes in which the peptide-binding domain was derived from human DR sequences whereas the CD4-binding domain was derived from mouse I-E sequences. Purified chimeric human/mouse MHC class II molecules were capable of specifically binding DR-restricted peptides. Human B cell transformants that expressed these chimeric MHC class II molecules could present peptide antigens to human T cell clones. Expression of these chimeric class II molecules in transgenic mice led to the intrathymic deletion of T cells expressing superantigen-reactive V beta 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-restricted immune responses after challenge with peptide or whole protein antigens. Thus, the chimeric class II molecules can serve as functional antigen presentation molecules in vivo. In addition, transgenic mice expressing chimeric class II molecules could be used to generate antigen-specific mouse T cell hybridomas that were capable of interacting with human antigen-presenting cells.

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