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-2Kb) linked to transcriptional control elements from the human beta-globin gene, which direct erythroid lineage specific transcription, express H-2Kb molecules in red blood cells but H-2Kb expression cannot be detected in skin or lymphoid cells. This limited pattern of self MHC expression is sufficient to induce tolerance to H-2Kb molecules and H-2Kb restricted cytotoxic T cell responses can be generated in transgenic mice. Transgenic mice are unable to mount H-2Kb specific cytotoxic T cell responses in vitro, even when exogenous IL-2 is provided. However, H-2Kb specific T cell proliferative responses are comparable with H-2Kb specific responses in non-transgenic mice, even in the absence of exogenous IL-2. Thus, expression of H-2Kb molecules under control of human beta-globin transcriptional control elements in transgenic mice is tolerogenic but does not result in elimination of all H-2Kb reactive T cells from the mature repertoire. This suggests that tolerance in these mice may arise due to functional inactivation of H-2Kb reactive T cells in vivo when they encounter H-2Kb molecules expressed on cells of erythroid cell lineages or on non-erythroid cells which express H-2Kb molecules at very low levels or in a developmentally regulated pattern. Furthermore, in spite of the failure to detect H-2Kb expression on non-erythroid cells in these mice, we conclude that H-2Kb molecules participate in positive selection of the T cell repertoire since H-2Kb restricted T cell responses can be generated in these transgenic mice.
Yeoman
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National Institute for Medical Research, Mill Hill, London, UK.
Mellor
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AL
D000818:Animals; D004912:Erythrocytes / Q000276:immunology; D015870:Gene Expression; D005805:Genes, MHC Class I; D005914:Globins / Q000235:genetics; D006183:H-2 Antigens / Q000235:genetics; D007108:Immune Tolerance / Q000235:genetics*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D011995:Recombination, Genetic; D013601:T-Lymphocytes / Q000276:immunology
D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D005914:Globins