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B Kinase 
in Thymic Organogenesis Required for the Establishment of Self-Tolerance1
* Department of Obstetrics and Gynecology and
Department of Molecular and Environmental Pathology, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima, Japan;
Division of Molecular Immunology, Institute for Enzyme Research, University of Tokushima, Tokushima, Japan;
Laboratory for Host Defense, Research Center for Allergy and Immunology, Kanagawa, Japan;
¶ Division of Bacterial and Blood Products, National Institute of Infectious Disease, Tokyo, Japan;
|| Division of Embryonic and Genetic Engineering, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan; and
# Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan
I
B kinase (IKK) 
exhibits diverse biological activities through protein kinase-dependent and -independent functions, the former mediated predominantly through a noncanonical NF-B activation pathway. The in vivo function of IKK, however, still remains elusive. Because a natural strain of mice with mutant NF-B-inducing kinase (NIK) manifests autoimmunity as a result of disorganized thymic structure with abnormal expression of Rel proteins in the thymic stroma, we speculated that the NIK-IKK axis might constitute an essential step in the thymic organogenesis that is required for the establishment of self-tolerance. An autoimmune disease phenotype was induced in athymic nude mice by grafting embryonic thymus from IKK-deficient mice. The thymic microenvironment that caused autoimmunity in an IKK-dependent manner was associated with defective processing of NF-B2, resulting in the impaired development of thymic epithelial cells. Thus, our results demonstrate a novel function for IKK in thymic organogenesis for the establishment of central tolerance that depends on its protein kinase activity in cooperation with NIK.
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