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From the Institut Necker, Institut National de la Santé et de la Recherche Médicale 373, F-75730 Paris, Cedex 15, France

Continuous antigenic stimulation in vivo can result in the generation of so-called "anergic" CD4⁺ or CD8⁺ T cells that fail to proliferate upon antigenic stimulation and fail to develop cytolytic effector functions. Here we show that class II major histocompatibility complex–restricted T cells specific for influenza hemagglutinin (HA) that become anergic in mice expressing HA under control of the immunoglobulin promoter exhibit an impaired effector function in causing diabetes in vivo, as compared to their naive counterparts, when transferred into immunodeficient recipients expressing HA under the control of the insulin promoter. Furthermore, HA-specific T cells anergized in vivo contain higher levels of interleukin (IL)-4 messenger RNA (mRNA) than naive and recently activated T cells with the same specificity and more than a 100-fold higher levels of IL-10 mRNA. The higher expression of the IL-10 gene is also evident at the protein level. These findings raise the interesting possibility that T cells rendered anergic in vivo have in fact become regulatory T cells that may influence neighboring immune responses through the release of IL-10.

J. Buer is supported by a grant from the Deutsche Forschungsgemeinschaft, A. Lanoue is a recipient of a grant from the Ministère de la Recherche et de l'Education, A. Franzke is supported by the Förderverein Tumorzentrum Niedersachsen, and H. von Boehmer is supported by the Institut Universitaire de France, by the Juvenile Diabetes Foundation, and by the Körber Foundation. This work was supported in part by the Institut National de la Santé et Recherche Médicale (Paris, France) and by the Faculté Necker Enfants Malades, Descartes Université (Paris, France).

A. Lanoue and J. Buer contributed equally to this work.

¹ Abbreviations used in this paper: AEC, 3-amino-9-ethyl-carbazole; ELISPOT, enzyme-linked immunospot; HA, hemagglutinin; HPRT, hypoxanthine guanine phosphoribosyltransferase; mRNA, messenger RNA; RAG, recombination activating gene; RT, reverse transcriptase.

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