The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1999/3/877/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 5, March 1, 1999 877-882

Brief Definitive Reports

Peripheral Autoantigen Induces Regulatory T Cells that Prevent Autoimmunity

Benedict Seddon and Don Mason

From the Medical Research Council Cellular Immunology Unit, Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RE, United Kingdom

Previous studies have shown that autoimmune thyroiditis can be induced in normal laboratory rats after thymectomy and split dose {gamma}-irradiation. Development of disease can be prevented by reconstitution of PVG rats shortly after their final irradiation with either peripheral CD4+CD45RC– T cells or CD4+CD8– thymocytes from syngeneic donors. Although the activity of both populations is known to depend on the activities of endogenously produced interleukin 4 and transforming growth factor β, implying a common mechanism, the issue of antigen specificity of the cells involved has not yet been addressed. In this study, we show that the regulatory T cells that prevent autoimmune thyroiditis are generated in vivo only when the relevant autoantigen is also present. Peripheral CD4+ T cells, from rats whose thyroids were ablated in utero by treatment with 131I, were unable to prevent disease development upon adoptive transfer into thymectomized and irradiated recipients. This regulatory deficit is specific for thyroid autoimmunity, since CD4+ T cells from 131I-treated PVG.RT1u rats were as effective as those from normal donors at preventing diabetes in thymectomized and irradiated PVG.RT1u rats. Significantly, in contrast to the peripheral CD4+ T cells, CD4+CD8– thymocytes from 131I-treated PVG donors were still able to prevent thyroiditis upon adoptive transfer. Taken together, these data indicate that it is the peripheral autoantigen itself that stimulates the generation of the appropriate regulatory cells from thymic emigrant precursors.

Key Words: autoimmunity • regulatory T cells • specificity • autoantigen

Address correspondence to Benedict P. Seddon, Division of Molecular Immunology, National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK. Phone: 44-181-959-3666, ext. 2209; Fax: 44-181-913-8531; E-mail: bseddon{at}nimr.mrc.ac.uk

Thanks are due to Liz Darley for preparation and staining of histological sections and to Steve Simmonds and Michael Puklavec for technical assistance.

Benedict Seddon is supported by a Wellcome Trust Prize Fellowship.


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