title: A p53 axis regulates B cell receptor-triggered, innate immune system-driven B cell clonal expansion.
abstract: Resting mature human B cells undergo a dynamic process of clonal expansion, followed by clonal contraction, during an in vitro response to surrogate C3d-coated Ag and innate immune system cytokines, IL-4 and BAFF. In this study, we explore the mechanism for clonal contraction through following the time- and division-influenced expression of several pro- and anti-apoptotic proteins within CFSE-labeled cultures. Several findings, involving both human and mouse B cells, show that a mitochondria-dependent apoptotic pathway involving p53 contributes to the high activation-induced cell death (AICD) susceptibility of replicating blasts. Activated B cell clones exhibit elevated p53 protein and elevated mRNA/protein of proapoptotic molecules known to be under direct p53 transcriptional control, Bax, Bad, Puma, Bid, and procaspase 6, accompanied by reduced anti-apoptotic Bcl-2. Under these conditions, Bim levels were not increased. The finding that full-length Bid protein significantly declines in AICD-susceptible replicating blasts, whereas Bid mRNA does not, suggests that Bid is actively cleaved to short-lived, proapoptotic truncated Bid. AICD was diminished, albeit not eliminated, by p53 small interfering RNA transfection, genetic deletion of p53, or Bcl-2 overexpression. DNA damage is a likely trigger for p53-dependent AICD because susceptible lymphoblasts expressed significantly elevated levels of both phosphorylated ataxia telangiectasia mutated-Ser(1980) and phospho-H2AX-Ser(139). Deficiency in activation-induced cytosine deaminase diminishes but does not ablate murine B cell AICD, indicating that activation-induced cytosine deaminase-induced DNA damage is only in part responsible. Evidence for p53-influenced AICD during this route of T cell-independent clonal expansion raises the possibility that progeny bearing p53 mutations might undergo positive selection in peripherally inflamed tissues with elevated levels of IL-4 and BAFF.
authors.affiliation: Laboratory of B Cell Biology, Karches Center for Chronic Lymphocytic Leukemia Research, Feinstein Institute for Medical Research, Manhasset, NY 11030, USA.
authors.forename: Hyunjoo
authors.initials: H
authors.lastname: Lee
authors.forename: Shabirul
authors.initials: S
authors.lastname: Haque
authors.forename: Jennifer
authors.initials: J
authors.lastname: Nieto
authors.forename: Joshua
authors.initials: J
authors.lastname: Trott
authors.forename: John K
authors.initials: JK
authors.lastname: Inman
authors.forename: Steven
authors.initials: S
authors.lastname: McCormick
authors.forename: Nicholas
authors.initials: N
authors.lastname: Chiorazzi
authors.forename: Patricia K A
authors.initials: PK
authors.lastname: Mongini
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D053264:B-Cell Activating Factor / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D049109:Cell Proliferation; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D034741:RNA, Small Interfering; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D053264:B-Cell Activating Factor; D034741:RNA, Small Interfering; D011947:Receptors, Antigen, B-Cell; D016159:Tumor Suppressor Protein p53; D015847:Interleukin-4