NF-κB-inducing kinase establishes self-tolerance in a thymic stroma-dependent manner

F Kajiura, S Sun, T Nomura, K Izumi… - The Journal of …, 2004 - journals.aai.org
F Kajiura, S Sun, T Nomura, K Izumi, T Ueno, Y Bando, N Kuroda, H Han, Y Li…
The Journal of Immunology, 2004journals.aai.org
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-κB-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 …
Abstract
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-κB-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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