NF-κB2 is required for the establishment of central tolerance through an Aire-dependent pathway

Mingzhao Zhu, Robert K. Chin, Peter A. Christiansen, James C. Lo, Xiaojuan Liu, Carl Ware, Ulrich Siebenlist, Yang Xin Fu

Research output: Contribution to journalArticle

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Abstract

NF-κB2-deficient mice have impaired T and B cell responses. We found, however, that in these mice there was severe infiltration of lymphocytes into multiple organs and increased activity of autoantibodies to peripheral tissue antigens in a manner similar to that of autoimmune regulator-deficient (Aire-deficient) mice. We further demonstrated that NF-κB2 was required for thymic Aire gene transcriptional regulation. The Nfkb2-/- thymus had distinct cortical and medullar structures, but reduced Aire and target gene expression of peripheral tissue antigens. Engraftment of Nfkb2-/- thymic stroma to nude mice recapitulated the autoimmune phenotype of the native Nfkb2-/- mice, confirming a key defect in central tolerance. Lymphotoxin β receptor (LTβR) ligation-induced Aire gene expression was also largely abolished in the absence of NF-κB2. Thus NF-κB2 downstream of LTβR plays an important role in the regulation of central tolerance in an Aire-dependent manner.

Original languageEnglish (US)
Pages (from-to)2964-2971
Number of pages8
JournalJournal of Clinical Investigation
Volume116
Issue number11
DOIs
StatePublished - Nov 1 2006

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Central Tolerance
Lymphotoxin-alpha
Gene Expression
Antigens
Nude Mice
Autoantibodies
Thymus Gland
Ligation
B-Lymphocytes
Lymphocytes
T-Lymphocytes
Phenotype
Genes

ASJC Scopus subject areas

  • Medicine(all)

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NF-κB2 is required for the establishment of central tolerance through an Aire-dependent pathway. / Zhu, Mingzhao; Chin, Robert K.; Christiansen, Peter A.; Lo, James C.; Liu, Xiaojuan; Ware, Carl; Siebenlist, Ulrich; Fu, Yang Xin.

In: Journal of Clinical Investigation, Vol. 116, No. 11, 01.11.2006, p. 2964-2971.

Research output: Contribution to journalArticle

Zhu, M, Chin, RK, Christiansen, PA, Lo, JC, Liu, X, Ware, C, Siebenlist, U & Fu, YX 2006, 'NF-κB2 is required for the establishment of central tolerance through an Aire-dependent pathway', Journal of Clinical Investigation, vol. 116, no. 11, pp. 2964-2971. https://doi.org/10.1172/JCI28326
Zhu, Mingzhao ; Chin, Robert K. ; Christiansen, Peter A. ; Lo, James C. ; Liu, Xiaojuan ; Ware, Carl ; Siebenlist, Ulrich ; Fu, Yang Xin. / NF-κB2 is required for the establishment of central tolerance through an Aire-dependent pathway. In: Journal of Clinical Investigation. 2006 ; Vol. 116, No. 11. pp. 2964-2971.
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AU - Ware, Carl

AU - Siebenlist, Ulrich

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