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TGF-1-Mediated Control of Central Nervous System Inflammation and Autoimmunity through the Inhibitory Receptor CD26¹

Vera Preller^*, Annegret Gerber^*, Sabine Wrenger^*, Mauro Togni^*, Didier Marguet, Janine Tadje, Uwe Lendeckel, Christoph Röcken, Jürgen Faust^¶, Klaus Neubert^¶, Burkhart Schraven^*, Roland Martin^||, Siegfried Ansorge^#, Stefan Brocke^2,**, and Dirk Reinhold^2,3,*

^* Institute of Immunology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; Centre d‘Immunologie de Marseille Luminy, Marseille, France; Institute of Experimental Internal Medicine, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; Institute of Pathology, Otto-von-Guericke-University Magdeburg, Magdeburg, Germany; ^¶ Institute of Biochemistry, Department of Biochemistry and Biotechnology, Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany; ^|| Cellular Immunology Section, Neuroimmunology Branch, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892; ^# IMTH GmbH, Magdeburg, Germany; ^** Department of Pathology, Hebrew University, Jerusalem, Israel; and Department of Pharmacology, University of Connecticut Health Center, Farmington, CT 06030

The T cell marker CD26/dipeptidyl peptidase (DP) IV is associated with an effector phenotype and markedly elevated in the human CNS disorder multiple sclerosis. However, little is known about the in vivo role of CD26/DP IV in health and disease, and the underlying mechanism of its function in CNS inflammation. To directly address the role of CD26/DP IV in vivo, we examined Th1 immune responses and susceptibility to experimental autoimmune encephalomyelitis in CD26^–/– mice. We show that gene deletion of CD26 in mice leads to deregulation of Th1 immune responses. Although production of IFN- and TNF- by pathogenic T cells in response to myelin Ag was enhanced in CD26^–/– mice, production of the immunosuppressive cytokine TGF-1 was diminished in vivo and in vitro. In contrast to the reduction in TGF-1 production, responsiveness to external TGF-1 was normal in T cells from CD26^–/– mice, excluding alterations in TGF-1 sensitivity as a mechanism causing the loss of immune regulation. Natural ligands of CD26/DP IV induced TGF-1 production in T cells from wild-type mice. However, natural ligands of CD26/DP IV failed to elicit TGF-1 production in T cells from CD26^–/– mice. The striking functional deregulation of Th1 immunity was also seen in vivo. Thus, clinical experimental autoimmune encephalomyelitis scores were significantly increased in CD26^–/– mice immunized with peptide from myelin oligodendrocyte glycoprotein. These results identify CD26/DP IV as a nonredundant inhibitory receptor controlling T cell activation and Th1-mediated autoimmunity, and may have important therapeutic implications for the treatment of autoimmune CNS disease.

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 (RE 1058/3-1) and the Land Sachsen-Anhalt (3521D/0703M and V 0604/00002). S.B. was supported by Grant 5063 from the Chief Scientist’s Office, Ministry of Health, Israel, and the Ministry of Science and Technology and Bundesministerium für Bildung und Forschung (1809).

² S.B. and D.R. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Dirk Reinhold, Institute of Immunology, Otto-von-Guericke-University Magdeburg, Leipziger Strasse 44, 39120 Magdeburg, Germany. E-mail address: dirk.reinhold{at}medizin.uni-magdeburg.de

⁴ Abbreviations used in this paper: DP, dipeptidyl peptidase; EAE, experimental autoimmune encephalomyelitis; FoxP3, forkhead-winged helix transcription factor; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis; TXA2-R, thromboxane A2 receptor; DS, downstream; US, upstream.

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