A role for the IκB family member bcl-3 in the control of central immunologic tolerance

Bcl-3 is a member of the family of I kappa B inhibitors. Unlike the classical, cytoplasmic I kappa Bs, Bcl-3 does not inhibit ReIA- or c-Rel-containing NF-kappa B transcription factor dimers. Instead, Bcl-3 can enter the nucleus and modulate NF-kappa B 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-kappa B2, 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-kappa B2 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-kappa B system to promote central tolerance in the thymus, in apparent contrast with the well-known roles of NF-kappa B to promote inflammation and autoimmunity in the periphery.