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J. Biol. Chem., Vol. 281, Issue 50, 38617-38624, December 15, 2006

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NF-B2 Is Required for the Control of Autoimmunity by Regulating the Development of Medullary Thymic Epithelial Cells^*

Baochun Zhang¹, Zhe Wang¹, Jane Ding, Pärt Peterson, William T. Gunning, and Han-Fei Ding²

From the Department of Biochemistry and Cancer Biology, Medical University of Ohio, Toledo, Ohio 43614 and Molecular Pathology, IGMP, Biomedicum, Ravila 19, University of Tartu, 50414 Tartu, Estonia

Medullary thymic epithelial cells function as antigen-presenting cells in negative selection of self-reactive T cell clones, a process essential for the establishment of central self-tolerance. These cells mirror peripheral tissues through promiscuous expression of a diverse set of tissue-restricted self-antigens. The genes and signaling pathways that regulate the development of medullary thymic epithelial cells are not fully understood. Here we show that mice deficient in NF-B2, a member of the NF-B family, display a marked reduction in the number of mature medullary thymic epithelial cells that express CD80 and bind the lectin Ulex europaeus agglutinin-1, leading to a significant decrease in the extent of promiscuous gene expression in the thymus of NF-B2^-/- mice. Moreover, NF-B2^-/- mice manifest autoimmunity characterized by multiorgan infiltration of activated T cells and high levels of autoantibodies to multiple organs. A subpopulation of the mice also develops immune complex glomerulonephritis. These findings identify a physiological function of NF-B2 in the development of medullary thymic epithelial cells and, thus, the control of self-tolerance induction.

Received for publication, July 14, 2006 , and in revised form, August 25, 2006.

^* This work was supported by American Cancer Society Grant RSG-03-173-01-CCG) and NCI, National Institutes of Health Grant R01 CA106550 (to H.-F. D.). 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 Both authors contributed equally to this work.

² To whom correspondence should be addressed: Dept. of Biochemistry and Cancer Biology, Medical University of Ohio, 3035 Arlington Ave., Toledo, OH 43614-5804. Tel.: 419-383-6653; Fax: 419-383-6228; E-mail: hding{at}meduohio.edu.

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