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B-Inducing Kinase Establishes Self-Tolerance in a Thymic Stroma-Dependent Manner1
,¶
* Division of Molecular Immunology, Institute for Enzyme Research, and
Department of Molecular and Environmental Pathology, School of Medicine, University of Tokushima, Tokushima, Japan;
Department of Experimental Pathology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan;
Division of Experimental Immunology, Institute for Genome Research, University of Tokushima, and Laboratory of Immune System Development, RIKEN-Research Center for Allergy and Immunology, Tokushima, Japan; and
¶ Laboratory for Immunopathology, RIKEN-Research Center for Allergy and Immunology, Yokohama, Japan
Physical contact between thymocytes and the thymic stroma is essential for T cell maturation and shapes the T cell repertoire in the periphery. Stromal elements that control these processes still remain elusive. We used a mouse strain with mutant NF-
B-inducing kinase (NIK) to examine the mechanisms underlying the breakdown of self-tolerance. This NIK-mutant strain manifests autoimmunity and disorganized thymic structure with abnormal expression of Rel proteins in the stroma. Production of immunoregulatory T cells that control autoreactive T cells was impaired in NIK-mutant mice. The autoimmune disease seen in NIK-mutant mice was reproduced in athymic nude mice by grafting embryonic thymus from NIK-mutant mice, and this was rescued by supply of exogenous immunoregulatory T cells. Impaired production of immunoregulatory T cells by thymic stroma without normal NIK was associated with altered expression of peripheral tissue-restricted Ags, suggesting an essential role of NIK in the thymic microenvironment in the establishment of central tolerance.
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