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Tolerance Of Class I Histocompatibility Antigens Expressed Extrathymically

G. Morahan, J. Allison, J. Miller
Published 1989 · Biology, Medicine

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ALTHOUGH convincing evidence has been obtained for the imposition of self-tolerance by the intrathymic deletion of self-reactive T cells1–4, the development of tolerance to antigens which are expressed only in the periphery is not so well understood. We have approached this question by creating transgenic mice5 which carry a class I major histocompatibility complex (MHC) gene (H-2Kb) linked to the rat insulin promoter6. Mice expressing the transgene develop diabetes, but do not appear to mount an immune response against the transgene-expressing pancreaticβ-cells, even when the transgene is allogeneic with respect to the endogenous host H-2 antigens6. We have now explored the mechanism of this tolerance further. We find that spleen cells from pre-diabetic transgenic (RIP-Kb) mice do not kill targets bearing H-2Kb, whereas thymus cells from the same mice do. The unresponsiveness of these spleen cells can be reversed in vitro by providing recombinant interleukin-2 (rIL-2). In older, diabetic mice, responsiveness develops as the pancreatic β-cells are lost. Our results point to an extrathymic mechanism of tolerance induction, dependent on the continuous presence of antigen and the lack of IL-2 in the local environment of potentially reactive T cells.
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