Peripheral tolerance to alloantigen results from altered regulation of the interleukin 2 pathway

doi:10.1084/jem.173.1.79

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Peripheral tolerance to alloantigen results from altered regulation of the interleukin 2 pathway

MJ Dallman, O Shiho, TH Page, KJ Wood and PJ Morris
Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Headington, England.

Tolerance to alloantigen may be induced in rats by administration of blood followed by transplantation of a renal allograft. The mechanism of this tolerance was investigated by directly analyzing the functional activity of graft-infiltrating cells. We have previously shown cytotoxic T lymphocyte infiltration of, and major histocompatibility complex induction on, grafts of tolerant animals. We now report that cells isolated from the grafts of tolerant rats show a reduced expression of the p55 interleukin 2 receptor (IL-2R) chain on the cell surface compared with that seen on the cells of untreated animals. Scatchard analysis further reveals low expression of high affinity IL- 2R. This is due to reduced transcription of both IL-2R alpha and beta chain mRNAs and results in a reduced ability of cells to proliferate in response to IL-2. Cells isolated from tolerant animals are unable to make biologically active IL-2 in culture, whereas cells from untreated animals make high levels. This is not reflected at the mRNA level as the IL-2 gene is induced in both tolerant and untreated animals to similar levels. The induction of tolerance is abrogated by administration of recombinant IL-2 to animals at the time of transplantation. Thus, we conclude that an altered regulation of the IL- 2 pathway results in tolerance in these alloantigen-treated and transplanted animals.
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