INDUCTION OF TOLERANCE TO SELF MHC CLASS-I MOLECULES EXPRESSED UNDER THE CONTROL OF MILK PROTEIN OR BETA-GLOBIN GENE PROMOTERS

We have studied tolerance induction in transgenic CBA mice expressing H-2K(b) genes under the influence of guinea-pig alpha-lactalbumin (KAL ) or human beta-globin gene promoter (Kbeta). KAL radioresistant cells , but not bone marrow derived cells, induce tolerance to H-2K(b) in ch imeric mice. In contrast, bone marrow derived and radio-resistant cell s of Kbeta mice induce tolerance. Although appropriate, tissue-specifi c, expression of H-2K(b) molecules occurs in KAL and Kbeta mice, H-2K( b) is expressed at low levels in thymus of transgenic mice. In additio n, dendritic cells and macrophages express H-2K(b) molecules when Kbet a, but not when KAL bone marrow is cultured in vitro. The mode of tole rance induction was examined in double transgenic mice by mating KAL o r Kbeta mice to mice expressing TCR transgenes (Tg-TCR) derived from a H-2K(b) specific, CD8-independent cytotoxic T cell clone. In both cas es, a large number of Tg-TCR+ CD8+CD4+ thymocytes develop but mature C D8+CD4- thymocytes fall to appear suggesting that thymocytes are elimi nated late in development. Some CD8-CD4- and CD8-CD4+ Tg-TCR+ T cells develop in double transgenic mice and respond to activation through th eir TCR-CD3 complex in vitro, although no responses to stimulation wit h H-2K(b) expressing cells were detected. Thus, tolerance induction in KAL and Kbeta mice proceeds via a deletional mechanism that is ineffi cient due either to low numbers of H-2K(b) expressing thymic cells or to the low levels of H-2K(b) expressed by thymic cells, or to a combin ation of these factors.