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 chimeric mice. In contrast, bone marrow derived and radio-resistant cells of Kbeta mice induce tolerance. Although appropriate, tissue-specific, 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 addition, dendritic cells and macrophages express H-2K(b) molecules when Kbeta, but not when KAL bone marrow is cultured in vitro. The mode of tolerance induction was examined in double transgenic mice by mating KAL or Kbeta mice to mice expressing TCR transgenes (Tg-TCR) derived from a H-2K(b) specific, CD8-independent cytotoxic T cell clone. In both cases, a large number of Tg-TCR+ CD8+CD4+ thymocytes develop but mature CD8+CD4- thymocytes fall to appear suggesting that thymocytes are eliminated late in development. Some CD8-CD4- and CD8-CD4+ Tg-TCR+ T cells develop in double transgenic mice and respond to activation through their TCR-CD3 complex in vitro, although no responses to stimulation with H-2K(b) expressing cells were detected. Thus, tolerance induction in KAL and Kbeta mice proceeds via a deletional mechanism that is inefficient 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 combination of these factors.