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

J Immunol. 2004 Feb 15;172(4):2067-75. doi: 10.4049/jimmunol.172.4.2067.

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-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoimmune Diseases / enzymology
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / pathology
  • Bone Marrow Transplantation / immunology
  • Bone Marrow Transplantation / pathology
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / transplantation
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Fetal Tissue Transplantation / immunology
  • Fetal Tissue Transplantation / pathology
  • Gene Expression Regulation, Developmental / immunology
  • Mice
  • Mice, Inbred A
  • Mice, Inbred BALB C
  • Mice, Mutant Strains
  • Mice, Nude
  • Mutation
  • NF-kappa B / biosynthesis*
  • NF-kappa B / physiology
  • NF-kappaB-Inducing Kinase
  • Organ Culture Techniques
  • Protein Serine-Threonine Kinases / biosynthesis
  • Protein Serine-Threonine Kinases / deficiency
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / physiology*
  • Receptors, Interleukin-2 / biosynthesis
  • Self Tolerance* / genetics
  • Stromal Cells / enzymology
  • Stromal Cells / immunology
  • Stromal Cells / transplantation
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / pathology
  • T-Lymphocyte Subsets / transplantation
  • Thymus Gland / embryology
  • Thymus Gland / enzymology*
  • Thymus Gland / immunology*
  • Thymus Gland / transplantation

Substances

  • NF-kappa B
  • Receptors, Interleukin-2
  • Protein Serine-Threonine Kinases