The NF-kB Regulator Bcl-3 Governs Dendritic Cell Antigen Presentation Functions in Adaptive Immunity

Bcl-3 is an atypical member of the IkB family and modulates gene expression via interaction with p50/NF-kB1 or p52/NF-kB2 homodimers. We report in the present study that Bcl-3 is required in dendritic cells (DCs) to assure effective priming of CD4 and CD8 T cells. Lack of Bcl-3 in bone marrow–derived DCs blunted their ability to expand and promote effector functions of T cells upon Ag/adjuvant challenge in vitro and after adoptive transfers in vivo. Importantly, the critical role of Bcl-3 for priming of T cells was exposed upon Ag/adjuvant challenge of mice specifically ablated of Bcl-3 in DCs. Furthermore, Bcl-3 in endogenous DCs was necessary for contact hypersensitivity responses. Bcl-3 modestly aided maturation of DCs, but most consequentially, Bcl-3 promoted their survival, partially inhibiting expression of several antiapoptotic genes. Loss of Bcl-3 accelerated apoptosis of bone marrow–derived DCs during Ag presentation to T cells, and DC survival was markedly impaired in the context of inflammatory conditions in mice specifically lacking Bcl-3 in these cells. Conversely, selective overexpression of Bcl-3 in DCs extended their lifespan in vitro and in vivo, correlating with increased capacity to prime T cells. These results expose a previously unidentified function for Bcl-3 in DC survival and the generation of adaptive immunity. D endritic cells (DCs) are the most potent APCs and are crucial for the initiation of adaptive immune responses. The immunogenicity of DCs is determined by their ability to capture, process, and present Ags, their production of cytokines and other soluble mediators, and their expression of costimulatory molecules, but also by their longevity. Enhanced survival or expansion of DCs can result in autoimmunity (1–3). Upon activation, the lifetime of DCs may need to be strictly regulated to maintain a balanced and functional immune response (4–6). However, how DCs manage to carefully control their own survival, particularly during priming of T cells, is largely unknown. NF-kB is a master regulator of inflammation, and several NF-kB subunits have been described to control DC functions (7–11). The dimeric NF-kB transcription factors are composed of five variously combined polypeptides that comprise the Rel/NF-kB family (RelA [p65], RelB, c-Rel, p50 [NF-kB1], and p52 [NF-kB2]). Both p50 and p52 lack transactivation domains, and the abundant p50 homodimers have been implicated in inhibition of NF-kB–dependent gene transcription (12, 13). NF-kB activity is regulated by the IkB family proteins, which include the classical members IkBa, IkBb, and IkBε, the p105/NF-kB1 and p100/NF-kB2 precursors, …