A role for the IkappaB family member Bcl-3 in the control of central immunologic tolerance.

Abstract

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.

• Authors: Xiaoren Zhang, Hongshan Wang, Estefania Claudio, Keith Brown, Ulrich Siebenlist
• Journal: Immunity (Immunity) Vol. 27 Issue 3 Pg. 438-52 (Sep 2007) ISSN: 1074-7613 [Print] United States
• PMID: 17869136 (Publication Type: Journal Article, Research Support, N.I.H., Intramural)

Chemical References

• B-Cell Lymphoma 3 Protein
• Bcl3 protein, mouse
• NF-kappa B p52 Subunit
• Proto-Oncogene Proteins
• Transcription Factors

Topics

• Adoptive Transfer
• Animals
• B-Cell Lymphoma 3 Protein
• Cell Differentiation (immunology)
• Epithelial Cells (cytology, immunology)
• Flow Cytometry
• Immune Tolerance
• Immunohistochemistry
• Inflammation (immunology)
• Liver (immunology, pathology)
• Lung (immunology, pathology)
• Mice
• Mice, Mutant Strains
• NF-kappa B p52 Subunit (immunology)
• Proto-Oncogene Proteins (immunology)
• Reverse Transcriptase Polymerase Chain Reaction
• Skin (immunology, pathology)
• Stromal Cells (immunology)
• T-Lymphocytes, Regulatory (cytology, immunology)
• Thymus Gland (cytology, immunology, pathology)
• Transcription Factors (immunology)