NF-kappaB2 is required for the establishment of central tolerance through an Aire-dependent pathway.
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.
Zhu
Mingzhao
M
Department of Pathology and Committee on Immunology, University of Chicago, Chicago, Illinois 60637, USA.
Chin
Robert K
RK
Christiansen
Peter A
PA
Lo
James C
JC
Liu
Xiaojuan
X
Ware
Carl
C
Siebenlist
Ulrich
U
Fu
Yang-Xin
YX
D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D007108:Immune Tolerance / Q000276:immunology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D053259:Lymphotoxin beta Receptor / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052003:NF-kappa B p52 Subunit / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D010641:Phenotype; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000276:immunology / Q000528:radiation effects; D017154:Stromal Cells / Q000276:immunology / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D000096927:AIRE Protein
D053645:Interleukin-2 Receptor alpha Subunit; D053259:Lymphotoxin beta Receptor; D052003:NF-kappa B p52 Subunit; D018124:Receptors, Tumor Necrosis Factor; D014157:Transcription Factors; D000096927:AIRE Protein