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IB Kinase 2/ Deficiency Controls Expansion of Autoreactive T Cells and Suppresses Experimental Autoimmune Encephalomyelitis¹

Bernhard Greve^*,, Robert Weissert^*, Nada Hamdi^*, Estelle Bettelli, Raymond A. Sobel^,, Anthony Coyle^2,¶, Vijay K. Kuchroo, Klaus Rajewsky^|| and Marc Schmidt-Supprian^3,||

^* Hertie Institute for Clinical Brain Research, Tübingen, Germany; Center for Neurologic Diseases, Harvard Medical School, Boston, MA 02115; Stanford University School of Medicine, Stanford, CA 94305; Veterans Affairs Health Care System, Palo Alto, CA 94304; ^¶ Millennium Pharmaceuticals, Cambridge, MA 02139; and ^|| CBR Institute for Biomedical Research, Harvard Medical School, Boston, MA 02115

The NF-B family of transcription factors plays a pivotal role in T cell activation and survival during (auto) immune responses. IB kinase 2/ (IKK2) is part of the IB kinase complex, a central component of the intracellular signaling pathway mediating NF-B activation. We studied the role of IKK2 in autoantigen-specific T cell activation and induction of autoimmune disease using mice that lack this kinase specifically in T cells (IKK2^{T cell} mice). We found highly impaired myelin-oligodendrocyte-glycoprotein (MOG)_35–55-specific T cell activation in vitro and complete resistance to MOG_35–55-induced experimental autoimmune encephalomyelitis (EAE) in IKK2^{T cell} C57BL/6 mice in vivo. By contrast, transgenic expression of a pathogenic MOG_35–55-specific TCR (2D2 TCR) rendered IKK2^{T cell} mice susceptible to MOG_35–55-induced EAE and restored in vitro MOG_35–55-specific T cell responses, indicating an expansion defect in IKK2-deficient T cells. Treatment with the IKK2-inhibitory compound PS-1145 reduced MOG_35–55-specific proliferation and cytokine production of 2D2 transgenic spleen cells in vitro and diminished clinical signs of EAE in vivo. Our data underscore the potential of therapeutic IKK inhibition in 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 study was supported by grants from the Deutsche Forschungsgemeinschaft GR1925/1-1 and 2-1 (to B.G.) and National Institutes of Health Grant AI057947 (to K.R.). R.W. holds Heisenberg Fellowship We 1947/4-2 from the Deutsche Forschungsgemeinschaft.

² Current address: MedImmune, One MedImmune Way, Gaithersburg, MD 20878.

³ Address correspondence and reprint requests to Dr. Marc Schmidt-Supprian, The CBR Institute for Biomedical Research, 200 Longwood Avenue, Boston, MA 02115. E-mail address: supprian{at}cbr.med.harvard.edu

⁴ Abbreviations used in this paper: IKK, IB kinase; NEMO, NF-B essential modulator; wt, wild type; T_R, T regulatory; MOG, myelin-oligodendrocyte-glycoprotein; EAE, experimental autoimmune encephalomyelitis; PDTC, pyrrolidine thiocarbamate; CM, cell medium; SPC, spleen cells; PI, propidium iodide; LNC, lymph node cell.