The Journal of Experimental Medicine
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Published 18 October 2004. doi:10.1084/jem.20041457
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 200, Number 8, 1039-1049
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Central Tolerance to Tissue-specific Antigens Mediated by Direct and Indirect Antigen Presentation

Alena M. Gallegos and Michael J. Bevan

Department of Immunology and Howard Hughes Medical Institute, University of Washington, Seattle, WA 98195

Address correspondence to Michael J. Bevan, Dept. of Immunology, University of Washington, Box 357370, Seattle, WA 98795. Phone: (206) 685-3610; Fax: (206) 685-3612; email: mbevan{at}u.washington.edu

Intrathymic expression of tissue-specific antigens (TSAs) by medullary thymic epithelial cells (Mtecs) leads to deletion of autoreactive T cells. However, because Mtecs are known to be poor antigen-presenting cells (APCs) for tolerance to ubiquitous antigens, and very few Mtecs express a given TSA, it was unclear if central tolerance to TSA was induced directly by Mtec antigen presentation or indirectly by thymic bone marrow (BM)-derived cells via cross-presentation. We show that professional BM-derived APCs acquire TSAs from Mtecs and delete autoreactive CD8 and CD4 T cells. Although direct antigen presentation by Mtecs did not delete the CD4 T cell population tested in this study, Mtec presentation efficiently deleted both monoclonal and polyclonal populations of CD8 T cells. For developing CD8 T cells, deletion by BM-derived APC and by Mtec presentation occurred abruptly at the transitional, CD4high CD8low TCRintermediate stage, presumably as the cells transit from the cortex to the medulla. These studies reveal a cooperative relationship between Mtecs and BM-derived cells in thymic elimination of autoreactive T cells. Although Mtecs synthesize TSAs and delete a subset of autoreactive T cells, BM-derived cells extend the range of clonal deletion by cross-presenting antigen captured from Mtecs.

Key Words: thymus • tolerance • tissue-specific antigen • cross-presentation • AIRE

Abbreviations used in this paper: AIRE, autoimmune regulator protein; Ctec, cortical thymic epithelial cell; DP, double positive; Mtec, medullary thymic epithelial cell; RIP, rat insulin promoter; SP, single positive; tec, thymic epithelial cell; TSA, tissue-specific antigen.


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