Thymus Medulla Formation and Central Tolerance Are Restored in IKKα−/− Mice That Express an IKKα Transgene in Keratin 5+ Thymic Epithelial Cells

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

NIK promotes tissue destruction independently of the alternative NF-κB pathway through TNFR1/RIP1-induced apoptosis

“…[50][51][52][53][54][55][56][57] As opposed to mTECs, cTEC number is not affected in mice with defect in the alternative NF-κB pathway. 58 However, in our study, we highlight a new role for NIK downstream of LTβR in induction of TNFR1-driven cTEC death and thymus involution.…”

Reduction in IκB Kinase α Expression Promotes the Development of Skin Papillomas and Carcinomas

“…Its involvement in the development of lymphoid organs and innate immunity requires IKK/NF-nB activity (3,4). IKKa also plays an essential role in the formation of the epidermis during embryonic development in mice (5)(6)(7).…”

Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

“…[1,13,14,[48][49][50] The thymus of Ikkα À/À newborns show reduced medullary regions and mTEC numbers. [35,36] Transplantation of Ikkα À/À thymuses to the kidney of nude mice only causes lymphocyte infiltration in the liver and pancreas, [36] suggesting that solely thymic epithelial-cell phenotypes are insufficient to elicit a severe systemic autoimmune disease, such as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) [25,30,51] -like disease in mice. Furthermore, in Ikkα KA/KA mice, IKKα inactivation impairs LTβR-, CD40-, or RANK-mediated canonical and noncanonical NF-kB activities in mTECs, resulting in significantly reduced mTEC numbers and downregulated Aire expression.…”

“…Severe autoimmunity and systemic autoinflammation Tumors in the esophagus and oral cavity/ fungal infection [25,35,36] Skin, lung, esophgeal, oral, and pancreatic cancer [15][16][17][18][19][20][21][22][23][24][25][26][27][28] www.advancedsciencenews.com www.bioessays-journal.com NF-kB pathways. [1,13,14,[48][49][50] The thymus of Ikkα À/À newborns show reduced medullary regions and mTEC numbers.…”

“…Canonical and noncanonical NF-kB molecules and their regulators IKKα, IKKβ, NIK, and TRAF6 are required for mTEC development through CD40, RANK, and LTβR of the TNFR family receptors ( Table 1). [25,[31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] Notably, excepting IKKα, mice deficient in these molecules develop impaired central tolerance-associated autoimmune diseases, but they do not display manifestations with increased fungal infection and carcinogenesis.…”