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Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells.

ABSTRACT: Long-lived antibody memory is mediated by the combined effects of long-lived plasma cells (PCs) and memory B cells generated in response to T cell-dependent antigens (Ags). IL-10 and IL-21 can activate multiple signaling pathways, including STAT1, STAT3, and STAT5; ERK; PI3K/Akt, and potently promote human B cell differentiation. We previously showed that loss-of-function mutations in STAT3, but not STAT1, abrogate IL-10- and IL-21-mediated differentiation of human naive B cells into plasmablasts. We report here that, in contrast to naive B cells, STAT3-deficient memory B cells responded to these STAT3-activating cytokines, differentiating into plasmablasts and secreting high levels of IgM, IgG, and IgA, as well as Ag-specific IgG. This was associated with the induction of the molecular machinery necessary for PC formation. Mutations in IL21R, however, abolished IL-21-induced responses of both naive and memory human B cells and compromised memory B cell formation in vivo. These findings reveal a key role for IL-21R/STAT3 signaling in regulating human B cell function. Furthermore, our results indicate that the threshold of STAT3 activation required for differentiation is lower in memory compared with naive B cells, thereby identifying an intrinsic difference in the mechanism underlying differentiation of naive versus memory B cells.

SUBMITTER: Deenick EK

PROVIDER: S-EPMC3832925 | biostudies-literature | 2013 Nov

REPOSITORIES: biostudies-literature

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Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells.

Deenick Elissa K EK Avery Danielle T DT Chan Anna A Berglund Lucinda J LJ Ives Megan L ML Moens Leen L Stoddard Jennifer L JL Bustamante Jacinta J Boisson-Dupuis Stephanie S Tsumura Miyuki M Kobayashi Masao M Arkwright Peter D PD Averbuch Diana D Engelhard Dan D Roesler Joachim J Peake Jane J Wong Melanie M Adelstein Stephen S Choo Sharon S Smart Joanne M JM French Martyn A MA Fulcher David A DA Cook Matthew C MC Picard Capucine C Durandy Anne A Klein Christoph C Holland Steven M SM Uzel Gulbu G Casanova Jean-Laurent JL Ma Cindy S CS Tangye Stuart G SG

The Journal of experimental medicine 20131111 12

Long-lived antibody memory is mediated by the combined effects of long-lived plasma cells (PCs) and memory B cells generated in response to T cell-dependent antigens (Ags). IL-10 and IL-21 can activate multiple signaling pathways, including STAT1, STAT3, and STAT5; ERK; PI3K/Akt, and potently promote human B cell differentiation. We previously showed that loss-of-function mutations in STAT3, but not STAT1, abrogate IL-10- and IL-21-mediated differentiation of human naive B cells into plasmablast ...[more]

PMID: 24218138

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Project description:BackgroundBoth antibody secreting cells (ASCs) and memory B cells are essential for the maintenance of humoral immunity. To date, limit studies have focused on the two populations in Kawasaki disease (KD). To address the status of humoral immunity during KD, our current concentration is on the variations of ASCs and memory B cells, as well as their subsets in both acute and remission stages of KD.MethodsASCs were defined as the population with high expressions of CD27 and CD38 among CD3-CD20- lymphocytes. Based on the expression of surface marker CD138 and intracellular marker IgG, ASCs were further divided into two subsets. Memory B cells were characterized by the expressions of IgD, CD27 and IgM, upon which memory B cells were further categorized into CD27 + IgD- (switched memory, Sm), CD27-IgD- (Double negative, DN) and CD27 + IgD + IgM+ (marginal zone, MZ) B cells. Collectively, six populations were analyzed using flow cytometry. The blood samples were collected from KD patients in different stages and healthy controls.ResultsIn the acute stage, the percentages of ASCs, CD138+ ASCs, and IgG+ ASCs were significantly increased. In contrast, the percentages of memory B cells including Sm and MZ B cells were significantly decreased. Correlation analysis found ASCs positively correlated with the level of serum IgM, whereas MZ B cells not only positively correlated with the level of serum IgG, IgA, and IgM, but also positively correlated with the level of serum complement C3 and C4 and negatively correlated with the value of C-reactive protein (CRP). In the remission stage, the percentages of IgG+ ASCs and MZ B cells were significantly reduced, whereas other subsets presented heterogeneous variations.ConclusionsOur study provided direct evidence that ASCs contributed to the pathogenesis of KD, and it was the first time to describe the variation of memory B cells in this disease. Among the subsets, only IgG+ ASCs presented a significant increase in the acute stage and decreased after IVIG administration, indicating the involvement of IgG+ ASCs in the inflammation of KD and also suggesting that IVIG played an inhibitory role in the expression of cytoplasmic IgG.

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Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells.

Publications

Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells.

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