TOLERANCE AND MHC RESTRICTION IN TRANSGENIC MICE EXPRESSING A MHC CLASS-I GENE IN ERYTHROID-CELLS

Transgenic mice carrying a MHC class I structural gene (H-2K(b)) linked to transcriptional control elements from the human beta-globin gene, which direct erythroid lineage specific transcription, express H-2K(b) molecules in red blood cells but H-2K(b) expression cannot be detected in skin or lymphoid cells. This limited pattern of self MHC expression is sufficient to induce tolerance to H-2K(b) molecules and H-2K(b) restricted cytotoxic T cell responses can be generated in transgenic mice. Transgenic mice are unable to mount H-2K(b) specific cytotoxic T cell responses in vitro, even when exogenous IL-2 is provided. However, H-2K(b) specific T cell proliferative responses are comparable with H-2K(b) specific responses in non-transgenic mice, even in the absence of exogenous IL-2. Thus, expression of H-2K(b) molecules under control of human beta-globin transcriptional control elements in transgenic mice is tolerogenic but does not result in elimination of all H-2K(b) reactive T cells from the mature repertoire. This suggests that tolerance in these mice may arise due to functional inactivation of H-2K(b) reactive T cells in vivo when they encounter H-2K(b) molecules expressed on cells of erythroid cell lineages or on non-erythroid cells which express H-2K(b) molecules at very low levels or in a developmentally regulated pattern. Furthermore, in spite of the failure to detect H-2K(b) expression on non-erythroid cells in these mice, we conclude that H-2K(b) molecules participate in positive selection of the T cell repertoire since H-2K(b) restricted T cell responses can be generated in these transgenic mice.