[Functional expression of xenogenic mixed isotype molecule, DR alpha E beta, in transgenic mice with HLA-DRA gene on X chromosome]

Abstract

A line of transgenic mice was established, in which HLA-DRA gene was integrated into the X chromosome and was stably transmitted to their progenies. The expression of DRA gene and immunological phenomena in the transgenic mice was investigated. 1) The DR alpha chain was associated with murine E beta b chain and xenogenic mixed isotype heterodimer DR alpha E beta b was expressed on immunocompetent cells, such as B cells, macrophages, dendritic cells, and thymic epithelial cells, despite that transgenic DRA gene contained only 268-bp of the 5'-flanking region. 2) The DR alpha E beta b molecules as well as E alpha E beta b functioned as major histocompatibility complex class II molecules to select T cell repertoire, to stimulate mixed lymphocyte reaction, and to induce proliferation of T cells specific to moth cytochrome c peptide (MCC 81-103). The 25% of amino acid substitutions between the DR alpha and the E alpha did not affect presentation of MCC 81-103 to T cell receptor (TCR) recognizing the peptide in the context of E alpha E beta b or E alpha E beta k. 3) In female mice hemizygous for HLA-DRA, the proportion of cells expressing the DR alpha E beta b molecules varied from one to another due to Lyonization. Clonal deletion of self-reactive T cells bearing TCR V beta 5 or V beta 11 was incomplete particularly when less than 20% of spleen cells were positive for DR alpha E beta b molecules. However, self-tolerance was acquired in these mice.