ZBTB38 is dispensable for hematopoiesis and antibody responses

Abstract

14Members of the broad complex, tram track, bric-a-brac and zinc finger (BTB-ZF) 15 family of transcription factors, such as BCL-6, ZBTB20, and ZBTB32, regulate antigen-16 specific B cell differentiation, plasma cell longevity, and the duration of antibody 17 production. We found that ZBTB38, a different member of the BTB-ZF family that binds 18 methylated DNA at CpG motifs, is highly expressed by germinal center B cells and 19 plasma cells. To define the functional role of ZBTB38 in B cell responses, we generated 20 mice conditionally deficient in this transcription factor. Germinal center B cells lacking 21 ZBTB38 dysregulated very few genes relative to wild-type and heterozygous littermate 22 controls. Accordingly, mice with hematopoietic-specific deletion of Zbtb38 showed 23 normal germinal center B cell numbers and antibody responses following immunization 24 with hapten-protein conjugates. Memory B cells from these animals functioned normally 25 in secondary recall responses. Despite expression of ZBTB38 in hematopoietic stem 26 cells, progenitors and mature myeloid and lymphoid lineages were also present in 27 normal numbers in mutant mice. These data demonstrate that ZBTB38 is dispensable 28 for hematopoiesis and antibody responses. These conditional knockout mice may 29 instead be useful in defining the functional importance of ZBTB38 in other cell types and 30 contexts. 31 32 33 34 35 3 36 Introduction 37 Antibody responses following infections or vaccinations are initiated by a series 38 of B cell activation steps and fate decisions [1]. Upon recognition of cognate antigens 39 and other stimulatory signals, B cells grow in size, express a panel of activation 40 markers, begin to proliferate, and a subset undergoes immunoglobulin isotype-switching 41 [2]. In T cell-dependent responses, B cells then differentiate either into antibody-42 secreting plasma cells or into germinal center B cells. Germinal centers are the sites in 43 which somatic hypermutation and affinity maturation occur and are under substantial 44 replicative and DNA damage-induced stress. Germinal centers eventually produce long-45 lived plasma cells (LLPCs) and memory B cells (MBCs), which have distinct antigen 46 specificities and mediate different aspects of immunity [3]. LLPCs constitutively secrete 47 antibodies and are important for providing protection against re-infection by the same 48 pathogen. Memory B cells, on the other hand, can only provide protection after re-49 activation by a cognate antigen through rapid differentiation into plasma cells. Recent 50 studies have identified the broad complex, tram track, bric-a-brac and zinc finger (BTB-51 ZF) family of transcription factors as key regulators in B cell development. BTB-ZF 52 family members bind DNA through its C-terminal zinc finger domains and recruit SMRT 53 co-repressors and histone deacetylases to N-terminal BTB/POZ domains [4-8]. Family 54 members that regulate distinct aspects of B cell-mediated immunity include BCL-6, 55 ZBTB20, and ZBTB32. BCL-6 is important for ...