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

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 Nfkb^2-/- 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.