Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells.
Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells.
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DOI：
10.1084/jem.20130323
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发表时间：
2013-11-18
期刊：
影响因子：
--
通讯作者：
Tangye SG
中科院分区：
文献类型：
--
作者：
Deenick EK;Avery DT;Chan A;Berglund LJ;Ives ML;Moens L;Stoddard JL;Bustamante J;Boisson-Dupuis S;Tsumura M;Kobayashi M;Arkwright PD;Averbuch D;Engelhard D;Roesler J;Peake J;Wong M;Adelstein S;Choo S;Smart JM;French MA;Fulcher DA;Cook MC;Picard C;Durandy A;Klein C;Holland SM;Uzel G;Casanova JL;Ma CS;Tangye SG
与幼稚B细胞不同，记忆B细胞需要降低水平的STAT 3活化以响应IL-10和IL-21分化成分泌抗体的浆母细胞;然而，该过程需要在幼稚细胞和记忆细胞中表达IL-21 R。长效抗体记忆是由长效浆细胞（PC）和响应T细胞依赖性抗原（Ags）产生的记忆B细胞的联合作用介导的。IL-10和IL-21可以激活多种信号通路，包括STAT 1、STAT 3和STAT 5; ERK; PI 3 K/Akt，并有效促进人B细胞分化。我们先前表明，STAT 3而不是STAT 1的功能缺失突变消除了IL-10和IL-21介导的人幼稚B细胞向浆母细胞的分化。我们在此报告，与幼稚B细胞相比，STAT 3缺陷型记忆B细胞对这些STAT 3激活细胞因子有反应，分化成浆母细胞并分泌高水平的IgM、IgG和伊加，以及Ag特异性IgG。这与诱导PC形成所必需的分子机制有关。然而，IL-21 R的突变消除了IL-21诱导的幼稚和记忆人B细胞的反应，并损害了体内记忆B细胞的形成。这些发现揭示了IL-21 R/STAT 3信号在调节人B细胞功能中的关键作用。此外，我们的研究结果表明，与幼稚B细胞相比，在记忆中分化所需的STAT 3激活阈值较低，从而鉴定了幼稚与记忆B细胞分化的内在机制差异。
Memory B cells, unlike naive B cells, require a reduced level of STAT3 activation to differentiate into antibody-secreting plasmablasts in response to IL-10 and IL-21; however, this process requires IL-21R expression in both naive and memory cells. 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.
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DOI：
10.4049/jimmunol.1102322
发表时间：
2012-04-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Davey AM;Pierce SK
通讯作者：
Pierce SK
影响因子：
20.3
作者：
Ellyard, JI;Avery, DT;Tangye, SG
通讯作者：
Tangye, SG
影响因子：
4.4
作者：
Good, Kim L.;Bryant, Vanessa L.;Tangye, Stuart G.
通讯作者：
Tangye, Stuart G.
DOI：
10.1073/pnas.0703872104
发表时间：
2007-08-14
影响因子：
11.1
作者：
Good, Kim L.;Tangye, Stuart G.
通讯作者：
Tangye, Stuart G.
影响因子：
7
作者：
Boisson-Dupuis S;Kong XF;Okada S;Cypowyj S;Puel A;Abel L;Casanova JL
通讯作者：
Casanova JL