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Thymus Medulla Formation and Central Tolerance Are Restored in IKK^–/– Mice That Express an IKK Transgene in Keratin 5⁺ Thymic Epithelial Cells¹

Department of Carcinogenesis, Science Park Research Division, University of Texas M. D. Anderson Cancer Center, Smithville, TX 78957

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-B pathway. In this study, we show that mTEC development is severely impaired and autoimmune manifestations occur in mice that are deficient in IB kinase (IKK), a required intermediate in the noncanonical NF-B signaling pathway. Introduction of an IKK transgene driven by a K5 promoter restores the K5⁺K14⁺ mTEC subset in IKK^–/– mice. Unexpectedly, the K5-IKK 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-IKK transgene ameliorates autoimmune symptoms in IKK^–/– mice. These data suggest that 1) medulla formation and central tolerance depend on activating the alternative NF-B 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant CA16672 from the National Institutes of Health and Grant ES07784 from the National Institute on Environmental Health Sciences.

² Address correspondence and reprint requests to Dr. Ellen Richie, Department of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Science Park Research Division, P.O. Box 389, 1808 Park Road 1C, Smithville, TX 78957. E-mail address: erichie{at}mdanderson.org

³ Abbreviations used in this paper: TEC, thymic epithelial cell; mTEC, medullary TEC; cTEC, cortical TEC; UEA-1, Ulex europaeus agglutinin-1; AIRE, autoimmune regulator; K5, keratin 5; IKK, IB kinase; Treg, regulatory T cell; DC, dendritic cell; TRA, tissue-restricted Ag; NIK, NF-B-inducing kinase; LTR, lymphotoxin receptor; ANA, antinuclear Ab.

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