The tumor promoter and NF-κB modulator Bcl-3 regulates splenic B cell development.
Bcl-3 is an atypical member of the family of IκB proteins. Unlike the classic members, Bcl-3 functions as a nuclear transcriptional cofactor that may, depending on context, promote or suppress genes via association with p50/NF-κB1 or p52/NF-κB2 homodimers. Bcl-3 is also an oncogene, because it is a partner in recurrent translocations in B cell tumors, resulting in deregulated expression. Bcl-3 functions, however, remain poorly understood. We have investigated the role of Bcl-3 in B cells and discovered a previously unknown involvement in the splenic development of these cells. Loss of Bcl-3 in B cells resulted in significantly more marginal zone (MZ) and fewer follicular (FO) B cells. Conversely, transgenic expression of Bcl-3 in B cells generated fewer MZ and more FO B cells. Both Bcl-3(-/-) FO and MZ B cells were more responsive to LPS stimulation compared with their wild-type counterparts, including increased proliferation. By contrast, Bcl-3(-/-) FO B cells were more prone to apoptosis upon BCR stimulation, also limiting their expansion. The data reveal Bcl-3 as a regulator of B cell fate determination, restricting the MZ path and favoring the FO pathway, at least in part, via increased signal-specific survival of the latter, a finding of relevance to its tumorigenic activity.
Laboratory of Molecular Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892.
Xiaoren
X
Zhang
Andrea
A
Paun
Estefania
E
Claudio
Hongshan
H
Wang
Ulrich
U
Siebenlist
D000818:Animals; D000944:Antigens, Differentiation, B-Lymphocyte / Q000032:analysis; D000081242:B-Cell Lymphoma 3 Protein; D016175:B-Lymphocyte Subsets / Q000737:chemistry / Q000166:cytology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D019070:Cell Lineage; D007113:Immunity, Innate; D007075:Immunoglobulin M / Q000276:immunology; D016130:Immunophenotyping; D039041:Integrin alpha4beta1 / Q000096:biosynthesis / Q000235:genetics; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count; D016169:Lymphocyte Function-Associated Antigen-1 / Q000096:biosynthesis / Q000235:genetics; D038041:Lymphopoiesis / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011828:Radiation Chimera; D013154:Spleen / Q000166:cytology* / Q000648:ultrastructure; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D000944:Antigens, Differentiation, B-Lymphocyte; D000081242:B-Cell Lymphoma 3 Protein; C000631345:Bcl3 protein, mouse; D007075:Immunoglobulin M; D039041:Integrin alpha4beta1; D008070:Lipopolysaccharides; D016169:Lymphocyte Function-Associated Antigen-1; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors