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Induction of Autoimmunity by Expansion of Autoreactive CD4⁺CD62L^low Cells In Vivo¹

Bastian Amend^2,*, Hong Doster^2,*, Christian Lange^*, Evelyn Dubois^*, Hubert Kalbacher, Arthur Melms^* and Felix Bischof^3,*

^* Hertie Institute for Clinical Brain Research, Department of General Neurology, University of Tübingen, Tübingen, Germany; and Medical and Natural Sciences Research Center, University of Tübingen, Tübingen, Germany

The prerequisites of peripheral activation of self-specific CD4⁺ T cells that determine the development of autoimmunity are incompletely understood. SJL mice immunized with myelin proteolipid protein (PLP) 139–151 developed experimental autoimmune encephalomyelitis (EAE) when pertussis toxin (PT) was injected at the time of immunization but not when injected 6 days later, indicating that PT-induced alterations of the peripheral immune response lead to the development of autoimmunity. Further analysis using IA^s/PLP_139–151 tetramers revealed that PT did not change effector T cell activation or regulatory T cell numbers but enhanced IFN- production by self-specific CD4⁺ T cells. In addition, PT promoted the generation of CD4⁺CD62L^low effector T cells in vivo. Upon adoptive transfer, these cells were more potent than CD4⁺CD62L^high cells in inducing autoimmunity in recipient mice. The generation of this population was paralleled by higher expression of the costimulatory molecules CD80, CD86, and B7-DC, but not B7-RP, PD-1, and B7-H1 on CD11c⁺CD4⁺ dendritic cells whereas CD11c⁺CD8⁺ dendritic cells were not altered. Collectively, these data demonstrate the induction of autoimmunity by specific in vivo expansion of CD4⁺CD62L^low cells and indicate that CD4⁺CD62L^low effector T cells and CD11c⁺CD4⁺ dendritic cells may be attractive targets for immune interventions to treat autoimmune diseases.

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 Gemeinnützige Hertie-Stiftung (1.01.1/04/006 to F.B. and A.M.), the Deutsche Forschungsgemeinschaft (BI 603/5-1 to F.B.), the Interdisciplinary Clinical Research Center (IZKF) Tübingen, Germany (to F.B.) and the Boehringer Ingelheim Fonds (to C.L.).

² B.A. and H.D. contributed equally to this work.

³ Address correspondence and reprint request to Dr. Felix Bischof, Hertie Institute for Clinical Brain Research, Department of General Neurology, University of Tübingen, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany. E-mail address: Felix.Bischof{at}uni-tuebingen.de

⁴ Abbreviations used in this paper: MS, multiple sclerosis; DC, dendritic cell; DLN, draining lymph node; EAE, experimental autoimmune encephalomyelitis; PLP, proteolipid protein; PT, pertussis toxin.