title: Regulation of germinal center responses and B-cell memory by the chromatin modifier MOZ.
abstract: Memory B cells and long-lived bone marrow-resident plasma cells maintain humoral immunity. Little is known about the intrinsic mechanisms that are essential for forming memory B cells or endowing them with the ability to rapidly differentiate upon reexposure while maintaining the population over time. Histone modifications have been shown to regulate lymphocyte development, but their role in regulating differentiation and maintenance of B-cell subsets during an immune response is unclear. Using stage-specific deletion of monocytic leukemia zinc finger protein (MOZ), a histone acetyltransferase, we demonstrate that mutation of this chromatin modifier alters fate decisions in both primary and secondary responses. In the absence of MOZ, germinal center B cells were significantly impaired in their ability to generate dark zone centroblasts, with a concomitant decrease in both cell-cycle progression and BCL-6 expression. In contrast, there was increased differentiation to IgM and low-affinity IgG1(+) memory B cells. The lack of MOZ affected the functional outcome of humoral immune responses, with an increase in secondary germinal centers and a corresponding decrease in secondary high-affinity antibody-secreting cell formation. Therefore, these data provide strong evidence that manipulating epigenetic modifiers can regulate fate decisions during humoral responses, and thus could be targeted for therapeutic intervention.
authors: Divisions of Immunology,Departments of Medical Biology and jacobson@wehi.edu.au tarlinton@wehi.edu.au.
authors: Kim L
authors: KL
authors: Good-Jacobson
authors: Departments of Medical Biology andBioinformatics, and.
authors: Yunshun
authors: Y
authors: Chen
authors: Departments of Medical Biology andDevelopment and Cancer, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; and.
authors: Anne K
authors: AK
authors: Voss
authors: Bioinformatics, andMathematics and Statistics, University of Melbourne, Parkville, VIC 3010, Australia.
authors: Gordon K
authors: GK
authors: Smyth
authors: Departments of Medical Biology andDevelopment and Cancer, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC 3052, Australia; and.
authors: Tim
authors: T
authors: Thomas
authors: Divisions of Immunology,Departments of Medical Biology and jacobson@wehi.edu.au tarlinton@wehi.edu.au.
authors: David
authors: D
authors: Tarlinton
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D002843:Chromatin / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D018858:Germinal Center / Q000276:immunology*; D051548:Histone Acetyltransferases / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology*; D051379:Mice; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D017423:Sequence Analysis, RNA; D018709:Statistics, Nonparametric
chemical_list: D002843:Chromatin; D051548:Histone Acetyltransferases; C511438:MOZ protein, mouse