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*Institut fuer Medizinische Mikrobiologie, Immunologie und Hygiene, Technische Universitaet Muenchen, Munich, Germany;
Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305;
Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research; a joint venture between the Medical School Hannover (MHH) and the Helmholtz Centre for Infection Research (HZI), Hannover, Germany;
Institut fuer Immunologie, Johannes Gutenberg-University Mainz, Mainz, Germany;
¶Experimental Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany;
||Institut fuer Pathologie/Research Center ImmunoSciences (RCIS), Charité Universitaetsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany;
#Laboratory of Lymphoid Tissue Development, Institute Pasteur, Paris, France;
**Institute for Immunology, Ludwig-Maximilians-University, Munich, Germany;
Department of Neuroimmunology, Max-Planck-Institute fuer Neurobiology, Martinsried, Germany, and Institute for Clinical Neuroimmunology, Ludwig Maximilians University, Klinikum Grosshadern, Munich, Germany;
*Helmholtz Zentrum für Infektionsforschung, Braunschweig, Germany; and
*Institut fuer Medizinische Mikrobiologie, Essen, Germany
Foxp3+ regulatory T cells (Tregs) are crucial for preventing autoimmunity. We have demonstrated that depletion of Foxp3+ Tregs results in the development of a scurfy-like disease, indicating that Foxp3– effector T cells are sufficient to induce autoimmunity. It has been postulated that nonfunctional Tregs carrying potentially self-reactive T cell receptors may contribute to scurfy (sf) pathogenesis due to enhanced recognition of self. Those cells, however, could not be identified in sf mutants due to the lack of Foxp3 protein expression. To address this issue, we crossed the natural sf mouse mutant with bacterial artificial chromosome transgenic DEREG (depletion of regulatory T cells) mice. Since DEREG mice express GFP under the control of an additional Foxp3 promoter, those crossings allowed proving the existence of "would-be" Tregs, which are characterized by GFP expression in the absence of functional Foxp3. Sf Tregs lost their in vitro suppressive capacity. This correlated with a substantial reduction of intracellular cAMP levels, whereas surface expression of Treg markers was unaffected. Both GFP+ and GFP– sf cells produced high amounts of Th2-type cytokines, reflected also by enhanced Gata-3 expression, when tested in vitro. Nevertheless, sf Tregs could be induced in vitro, although with lower efficiency than DEREG Tregs. Transfer of GFP+ sf Tregs, in contrast to GFP– sf T cells, into RAG1-deficient animals did not cause the sf phenotype. Taken together, natural and induced Tregs develop in the absence of Foxp3 in sf mice, which lack both suppressive activity and autoreactive potential, but rather display a Th2-biased phenotype.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Deutsche Forschungsgemeinschaft (SP 615/3-2, SFB/TR22, SFB/TR52, SFB548, SFB633, and SFB650), the Carl Zeiss Foundation, and by the Wilhelm Sander Foundation.
2 Address correspondence and reprint requests to Dr. Tim Sparwasser, Institute of Infection Immunology, TWINCORE, Centre for Experimental and Clinical Infection Research, Feodor-Lynen-Straße 7, 30625 Hannover, Germany. E-mail address: tim.sparwasser{at}twincore.de
3 Abbreviations used in this paper: sf, scurfy; BAC, bacterial artificial chromosome; DEREG, depletion of regulatory T cells; IPEX, immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome; LN, lymph node; Treg, regulatory T cell; WT, wild type.
4 The online version of this article contains supplemental material.
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