A role for the IkappaB family member Bcl-3 in the control of central immunologic tolerance.
Bcl-3 is a member of the family of IkappaB inhibitors. Unlike the classical, cytoplasmic IkappaBs, Bcl-3 does not inhibit RelA- or c-Rel-containing NF-kappaB transcription factor dimers. Instead, Bcl-3 can enter the nucleus and modulate NF-kappaB activity, although the underlying mechanism and physiologic function remain largely unknown. Here we identified Bcl-3 as a regulator of immunologic tolerance to self. In parallel with NF-kappaB2, Bcl-3 functions within stroma to generate medullary thymic epithelial cells, which are essential for negative selection of autoreactive T cells. Loss of both NF-kappaB2 and Bcl-3, but not either one alone, led to a profound breakdown in central tolerance resulting in rapid and fatal multiorgan inflammation. These data reveal extensive utilization of the NF-kappaB system to promote central tolerance in the thymus, in apparent contrast with the well-known roles of NF-kappaB to promote inflammation and autoimmunity in the periphery.
Zhang
Xiaoren
X
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Wang
Hongshan
H
Claudio
Estefania
E
Brown
Keith
K
Siebenlist
Ulrich
U
D019264:Adoptive Transfer; D000818:Animals; D000081242:B-Cell Lymphoma 3 Protein; D002454:Cell Differentiation / Q000276:immunology; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology; D005434:Flow Cytometry; D007108:Immune Tolerance; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology*; D008099:Liver / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D008817:Mice, Mutant Strains; D052003:NF-kappa B p52 Subunit / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000276:immunology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000276:immunology / Q000473:pathology; D017154:Stromal Cells / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D014157:Transcription Factors / Q000276:immunology*
D000081242:B-Cell Lymphoma 3 Protein; C000631345:Bcl3 protein, mouse; D052003:NF-kappa B p52 Subunit; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors