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Origin of regulatory T cells with known specificity for antigen

Abstract

T cell receptor agonists can induce the differentiation of regulatory T (TR) cells. We report here that the immunoglobulin κ–controlled expression of an agonist in different cell types correlated with the phenotype of the generated TR cells. We found that aberrant expression on thymic stroma yielded predominantly CD4+CD25+ TR cells, which—under physiological conditions—may be induced by ectopically expressed organ-specific antigens and thus prevent organ-specific autoimmunity. Expression of the agonist antigen by nonactivated hematopoietic cells produced mostly CD4+CD25 TR cells. This subset can be derived from mature monospecific T cells without “tutoring” by other T cells and can be generated in the absence of a functioning thymus. Suppression of CD4+ T cell proliferative responses by both CD25+ and CD25 subsets was interleukin 10 (IL-10)–independent and was overcome by IL-2. These data suggest that distinct pathways can be exploited to interfere with unwanted immune responses.

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Figure 1: Development of TCR-transgenic CD25+ and CD25 regulatory cells in TCR-HA+Ig-HA+ mice.
Figure 2: CD25+ and CD25CD4+ cells from TCR-HA+Ig-HA+ mice are regulatory in vivo.
Figure 3: Development of TCR-transgenic CD25+ and CD25 TR cells in RAG-2−/− TCR-HA+Ig-HA+ mice.
Figure 4: HA expression by thymic stromal cell subsets.
Figure 5: HA-expressing hematopoietic cells induce both CD25+ and CD25 6.5+CD4+ TR cells.
Figure 6: Peripheral 6.5+CD4+ T cells from RAG-2−/− TCR-HA+ mice become regulatory upon prolonged antigenic stimulation.
Figure 7: Expression of HA by TECs induces CD25+CD4+ cells.

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Acknowledgements

Supported by the Fondation pour la Recherche Médicale and Millenium Pharmaceuticals, Inc. (I. A.), The Deutsche Forschungsgemeinschaft (grant LK1228/1-1 to L. K.) and the Juvenile Diabetes Research Foundation International (H. v. B.).

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Correspondence to Harald von Boehmer.

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Apostolou, I., Sarukhan, A., Klein, L. et al. Origin of regulatory T cells with known specificity for antigen. Nat Immunol 3, 756–763 (2002). https://doi.org/10.1038/ni816

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