Thymus Medulla Formation and Central Tolerance Are Restored in Ikkalpha-/- Mice That Express an Ikkalpha Transgene in Keratin 5+ Thymic Epithelial Cells.
From: Department of Carcinogenesis, Science Park Research Division, University of Texas M. D. Anderson Cancer Center, 1808 Park Road 1C, Smithville, TX 78957, USA.
Journal of immunology (Baltimore, Md. : 1950)
- Publish Date: Jan 2007
- ISSN: 0022-1767
- Volume: 178
- Issue: 2
- Pages: 829-37
- Medium: Print
- Language: English
- Citation (JAMA): Lomada Dakshayani, Liu Bigang, Coghlan Lezlee, et al. Thymus Medulla Formation and Central Tolerance Are Restored in Ikkalpha-/- Mice That Express an Ikkalpha Transgene in Keratin 5+ Thymic Epithelial Cells.. J. Immunol. Jan 2007;178:829-37
Abstract
Medullary thymic epithelial cells (mTECs) play an essential role in establishing central tolerance due to their unique capacity to present a diverse array of tissue restricted Ags that induce clonal deletion of self-reactive thymocytes. One mTEC subset expresses keratin 5 (K5) and K14, but fails to bind Ulex europaeus agglutinin-1 (UEA-1) lectin. A distinct mTEC subset binds UEA-1 and expresses K8, but not K5 or K14. Development of both mTEC subsets requires activation of the noncanonical NF-kappaB pathway. In this study, we show that mTEC development is severely impaired and autoimmune manifestations occur in mice that are deficient in IkappaB kinase (IKK)alpha, a required intermediate in the noncanonical NF-kappaB signaling pathway. Introduction of an IKKalpha transgene driven by a K5 promoter restores the K5(+)K14(+) mTEC subset in IKKalpha(-/-) mice. Unexpectedly, the K5-IKKalpha transgene also rescues the UEA-1 binding mTEC subset even though K5 expression is not detectable in these cells. In addition, expression of the K5-IKKalpha transgene ameliorates autoimmune symptoms in IKKalpha(-/-) mice. These data suggest that 1) medulla formation and central tolerance depend on activating the alternative NF-kappaB signaling pathway selectively in K5-expressing mTECs and 2) the K5-expressing subset either contains immediate precursors of UEA-1 binding cells or indirectly induces their development.
Mesh Headings (Keywords): Animals, Cell Differentiation, Dendritic Cells, Epithelial Cells, Gene Expression Regulation, I-kappa B Kinase, Immune Tolerance, Keratin-5, Mice, Mice, Knockout, Promoter Regions (Genetics), Thymus Gland, Transgenes
Check for Full Text / PubMed Unique Identifier (PMID): 17202344
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