Abstract
Members of the broad complex, tram track, bric-a-brac and zinc finger (BTB-ZF) family of transcription factors, such as BCL-6, ZBTB20, and ZBTB32, regulate antigen-specific B cell differentiation, plasma cell longevity, and the duration of antibody production. We found that ZBTB38, a different member of the BTB-ZF family that binds methylated DNA at CpG motifs, is highly expressed by germinal center B cells and plasma cells. To define the functional role of ZBTB38 in B cell responses, we generated mice conditionally deficient in this transcription factor. Germinal center B cells lacking ZBTB38 dysregulated very few genes relative to wild-type and heterozygous littermate controls. Accordingly, mice with hematopoietic-specific deletion of Zbtb38 showed normal germinal center B cell numbers and antibody responses following immunization with hapten-protein conjugates. Memory B cells from these animals functioned normally in secondary recall responses. Despite expression of ZBTB38 in hematopoietic stem cells, progenitors and mature myeloid and lymphoid lineages were also present in normal numbers in mutant mice. These data demonstrate that ZBTB38 is dispensable for hematopoiesis and antibody responses. These conditional knockout mice may instead be useful in defining the functional importance of ZBTB38 in other cell types and contexts.
Highlights
Antibody responses following infections or vaccinations are initiated by a series of B cell activation steps and fate decisions [1]
Wild-type mice were immunized with alhydrogeladjuvanted 4-hydroxy-3-nitrophenyl-acetyl (NP) conjugated to ovalbumin (OVA) and naïve B cells (CD19+CD138-GL7-IgD+), NP-specific dark (CXCR4+) and light zone (CD86+) germinal center (GC) B cells (CD19+GL7+IgD-), and NP-specific splenic plasma cells (CD138+) were sorted 11 days after immunization [33]
GC B cells and splenic plasma cells contained 9and 3-fold, respectively, higher expression of ZBTB38 compared to naïve B cells (Fig 1B; S1 Fig)
Summary
Antibody responses following infections or vaccinations are initiated by a series of B cell activation steps and fate decisions [1]. Upon recognition of cognate antigens and other stimulatory signals, B cells grow in size, express a panel of activation markers, begin to proliferate, and a subset undergoes immunoglobulin isotype-switching [2]. In T cell-dependent responses, B cells differentiate either into antibody-secreting plasma cells or into germinal center B cells. Germinal centers eventually produce long-lived plasma cells (LLPCs) and memory B cells (MBCs), which have distinct antigen specificities and mediate different aspects of immunity [3]. LLPCs constitutively secrete antibodies and are important for providing protection against re-infection by the same pathogen. Memory B cells, on the other hand, can only provide protection after re-activation by a cognate antigen through rapid differentiation into plasma cells or secondary
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