NF-kappa B-inducing kinase establishes self-tolerance in a thymic stroma-dependent manner.
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-kappaB-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.
Kajiura
Fumiko
F
Department of Molecular and Environmental Pathology, School of Medicine, University of Tokushima, Tokushima, Japan.
Sun
Shijie
S
Nomura
Takashi
T
Izumi
Keisuke
K
Ueno
Tomoo
T
Bando
Yoshimi
Y
Kuroda
Noriyuki
N
Han
Hongwei
H
Li
Yi
Y
Matsushima
Akemi
A
Takahama
Yousuke
Y
Sakaguchi
Shimon
S
Mitani
Tasuku
T
Matsumoto
Mitsuru
M
D000818:Animals; D001327:Autoimmune Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D016332:Fetal Tissue Transplantation / Q000276:immunology / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000276:immunology; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D008819:Mice, Nude; D009154:Mutation; D016328:NF-kappa B / Q000096:biosynthesis* / Q000502:physiology; D009924:Organ Culture Techniques; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D017634:Self Tolerance / Q000235:genetics; D017154:Stromal Cells / Q000201:enzymology / Q000276:immunology / Q000637:transplantation; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D013950:Thymus Gland / Q000196:embryology / Q000201:enzymology* / Q000276:immunology* / Q000637:transplantation; D000097782:NF-kappaB-Inducing Kinase
D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D015375:Receptors, Interleukin-2; D000097782:NF-kappaB-Inducing Kinase