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Chronic Antigen Stimulation In Vivo Induces a Distinct Population of Antigen-Specific Foxp3^–CD25^– Regulatory T Cells¹

Wiebke Hansen^2,*, Astrid M. Westendorf, Simone Reinwald, Dunja Bruder, Stefanie Deppenmeier, Lothar Groebe, Michael Probst-Kepper, Achim D. Gruber, Robert Geffers and Jan Buer^*

^* Institute of Medical Microbiology, University Hospital Essen, Essen, Germany; Department of Mucosal Immunity, Helmholtz Centre for Infection Research, Braunschweig, Germany; Department of Veterinary Pathology, Free University, Berlin, Germany; and Junior Research Group for Xenotransplantation, Department of Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany

The concept of immune regulation/suppression has been well-established and, besides thymus-derived CD4⁺CD25⁺ regulatory T (T_R) cells, it became clear that a variety of additional peripherally induced T_R cells play vital roles in protection from many harmful immune responses including intestinal inflammation. In the present study, we have analyzed in vivo-induced Ag-specific CD4⁺ T_R cells with respect to their molecular and functional phenotype. By comparative genomics we could show that these Ag-specific T_R cells induced by chronic Ag stimulation in vivo clearly differ in their genetic program from naturally occurring thymus-derived CD4⁺CD25⁺ T_R cells. This distinct population of induced T_R cells express neither CD25 nor the T_R-associated transcription factor Foxp3. Strikingly, CD25 is not even up-regulated upon stimulation. Despite the lack in Foxp3 expression, these in vivo-induced CD25^– T_R cells are able to interfere with an Ag-specific CD8⁺ T cell-mediated intestinal inflammation without significant increase in CD25 and Foxp3 expression. Thus, our results demonstrate that in vivo-induced Ag-specific T_R cells represent a distinct population of Foxp3^–CD25^– T_R cells with regulatory capacity both in vitro and in vivo.

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 grants from the Deutsche Forschungsgemeinschaft to J.B. and D.B. (SFB621).

² Address correspondence and reprint requests to Dr. Wiebke Hansen, Institute of Medical Microbiology, University Hospital Essen, Hufelandstrasse 55, D-45122 Essen, Germany. E-mail address: wiebke.hansen{at}uk-essen.de

³ Abbreviations used in this paper: T_R, regulatory T; HA, hemagglutinin; GITR, glucocorticoid-induced TNFR; Nrp1, neuropilin 1; GPR, G protein-coupled receptor; CBA, cytometric bead array; LPL, lamina propria lymphocyte; MLN, mesenteric lymph node; dtg, double transgenic; stg, single transgenic; WT, wild type; DC, dendritic cell; T_N, naive T.