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J Clin Invest. 2006 Nov;116(11):2964-71. Epub 2006 Oct 12.

NF-kappaB2 is required for the establishment of central tolerance through an Aire-dependent pathway.

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Department of Pathology and Committee on Immunology, University of Chicago, Chicago, Illinois 60637, USA.


NF-kappaB2-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-kappaB2 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 beta receptor (LTbetaR) ligation-induced Aire gene expression was also largely abolished in the absence of NF-kappaB2. Thus NF-kappaB2 downstream of LTbetaR plays an important role in the regulation of central tolerance in an Aire-dependent manner.

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