Inhibition of Terminal Differentiation of B Cells Mediated by CD27 and CD40 Involves Signaling through JNK
Inhibition of Terminal Differentiation of B Cells Mediated by CD27 and CD40 Involves Signaling through JNK
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DOI：
10.4049/jimmunol.0903229
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发表时间：
2010-12
期刊：
影响因子：
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通讯作者：
Shuchismita R. Satpathy;Gautam N. Shenoy;Sheetal Kaw;Tushar Vaidya;V. Bal;S. Rath;A. George
中科院分区：
文献类型：
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作者：
Shuchismita R. Satpathy;Gautam N. Shenoy;Sheetal Kaw;Tushar Vaidya;V. Bal;S. Rath;A. George
在体内，对同种抗原反应的B细胞经历克隆扩增，然后分化为分泌抗体的浆细胞或静态的可再刺激记忆。这两个事件都发生在生发中心，并要求细胞退出增殖，但导致这些相互排斥的分化途径之一的信号还没有确定的特征。以前的实验表明，在体外或体内B细胞刺激时，通过TNFR CD27和CD40转导的信号可以通过抑制终末分化和促进记忆来影响这种细胞命运的决定。在这项研究中，我们发现小鼠CD27胞浆尾部的PIQED结构域和适配分子TNFR相关因子2参与了这一效应。使用信号中间产物的药理抑制剂，我们确认JNK对于观察到的终端分化抑制是必要的和充分的。虽然JNK参与了CD40的下游，但抑制MEK通路也可以部分恢复浆细胞的生成，这表明这两个信号中间体可能都参与了这一过程。我们还表明，抑制干扰素调节因子4和B淋巴细胞诱导成熟蛋白1的诱导是这两种受体共同的下游事件。
B cells responding to cognate Ag in vivo undergo clonal expansion that is followed by differentiation into Ab-secreting plasma cells or into quiescent restimulable memory. Both these events occur in the germinal center and require that cells exit from proliferation, but the signals that lead to one or the other of these mutually exclusive differentiation pathways have not been definitively characterized. Previous experiments have shown that signals transduced through the TNFRs CD27 and CD40 at the time of B cell stimulation in vitro or in vivo can influence this cell fate decision by inhibiting terminal differentiation and promoting memory. In this study, we show that the PIQED domain of the cytoplasmic tail of murine CD27 and the adapter molecule TNFR-associated factor 2 are involved in this effect. Using pharmacological inhibitors of signaling intermediates, we identify JNK as being necessary and sufficient for the observed inhibition of terminal differentiation. While JNK is involved downstream of CD40, inhibition of the MEK pathway can also partially restore plasma cell generation, indicating that both signaling intermediates may be involved. We also show that inhibition of induction of IFN regulatory factor 4 and B lymphocyte induced maturation protein 1 are downstream events common to both receptors.