Deleted in Breast Cancer 1 (DBC1) Suppresses B cell Activation by Negatively Regulating the Alternative NFkappaB Signaling Pathway

The regulation of B cell activation is crucial for maintaining optimal humoral response, while avoiding production of autoantibodies. B cell Activating Factor Receptor (BAFFR) and CD40 have been implicated as key regulators of peripheral B cells. Both CD40 and BAFFR are members of the Tumor Necrosis Factor Receptor (TNFR) family, and signal through the Nuclear Factor kappa B (NFkappaB) pathway. Interestingly, both CD40 and BAFFR are able to signal through one or both branches of the NFkappaB pathway, i.e. canonical and alternative branches. How CD40 and BAFFR selectively signal to one branch over the other is not fully understood.;Deleted in Breast Cancer 1 (DBC1) is a putative tumor suppressor, but its role in the immune response has not been characterized. In this thesis we identify DBC1 as a novel regulator of B cell activation by selectively suppressing the alternative NFkappaB pathway. B cells isolated from mice with a global deletion of DBC1 (DBC1 KO) exhibit enhanced proliferation and immunoglobulin production in vitro upon CD40 and BAFFR, but not BCR and LPS stimulation. Bone marrow chimera experiments further demonstrate that DBC1 suppresses B cell activation in a cell-intrinsic manner. Microarray analysis reveals that loss of DBC1 results in dysregulation of NFkappaB target genes. DNA-pull down assay and Chromatin Immunoprecipitation (ChIP) experiments further determine that DBC1 selectively suppresses the activity of alternative NFkappaB members, RelB and p52. As a result of the loss of DBC1 regulation in B cells, when immunized with Nitrophenylated-Keyhole Limpet Hemocyanin (NP-KLH) without adjuvant, DBC1 KO mice produce significantly increased levels of antigen-specific immunoglobulin. Furthermore, dysregulated production of immunoglobulin results in increased levels of self-reactive antibody in DBC1 KO mice, when immunized with NP-KLH without adjuvant, as well as spontaneously after 10 months of age. Finally, loss of DBC1 in mice leads to higher susceptibility to Experimental Autoimmune Myasthenia Gravis (EAMG). In sum, work from this thesis identifies a novel role of DBC1 as a suppressor of B cell activation by negatively regulating the alternative NFkappaB pathway.