Abstract
Generation of specific antibodies during an immune response to infection or vaccination depends on the ability to rapidly and accurately select clones of antibody-secreting B lymphocytes for expansion. Antigen-specific B cell clones undergo the cell fate decision to differentiate into antibody-secreting plasma cells, memory B cells, or germinal center B cells. The E26-transformation-specific (ETS) transcription factors Spi-B and Spi-C are important regulators of B cell development and function. Spi-B is expressed throughout B cell development and is downregulated upon plasma cell differentiation. Spi-C is highly related to Spi-B and has similar DNA-binding specificity. Heterozygosity for Spic rescues B cell development and B cell proliferation defects observed in Spi-B knockout mice. In this study, we show that heterozygosity for Spic rescued defective IgG1 secondary antibody responses in Spib–/– mice. Plasma cell differentiation was accelerated in Spib–/– B cells. Gene expression, ChIP-seq, and reporter gene analysis showed that Spi-B and Spi-C differentially regulated Bach2, encoding a key regulator of plasma cell and memory B cell differentiation. These results suggest that Spi-B and Spi-C oppose the function of one another to regulate B cell differentiation and function.
Highlights
Naïve B cells possess the capacity to differentiate into heterogeneous cellular subsets that promote the resolution of both current and future infections
We sought to determine whether heterozygosity for Spic could rescue the impairment in antibodysecreting cell (ASC) frequencies in Spib−/− mice on a C57BL/6 background immunized with NP conjugated to ovalbumin (OVA)
Our results demonstrate that Spi-B and Spi-C play opposing roles in secondary antibody responses and plasmablast differentiation
Summary
Naïve B cells possess the capacity to differentiate into heterogeneous cellular subsets that promote the resolution of both current and future infections. These subsets include Plasma Cells (PC), memory B cells, and germinal center (GC) B cells [1, 2]. Within the dark zone of the GC, rapidly cycling B cells accumulate point mutations in the variable regions of BCR-encoding immunoglobulin genes [5]. This stochastic process, known as somatic hypermutation, diversifies the range of antigenic affinities exhibited by GC B cells [6].
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