Am. Sponaas et al., INDUCTION OF TOLERANCE TO SELF MHC CLASS-I MOLECULES EXPRESSED UNDER THE CONTROL OF MILK PROTEIN OR BETA-GLOBIN GENE PROMOTERS, International immunology, 6(2), 1994, pp. 277-287
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.