A balance between B cell receptor and inhibitory receptor signaling controls plasma cell differentiation by maintaining optimal Ets1 levels.
A balance between B cell receptor and inhibitory receptor signaling controls plasma cell differentiation by maintaining optimal Ets1 levels.
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DOI：
10.4049/jimmunol.1400666
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发表时间：
2014-07-15
期刊：
影响因子：
--
通讯作者：
Garrett-Sinha LA
中科院分区：
文献类型：
--
作者：
Luo W;Mayeux J;Gutierrez T;Russell L;Getahun A;Müller J;Tedder T;Parnes J;Rickert R;Nitschke L;Cambier J;Satterthwaite AB;Garrett-Sinha LA
通过B细胞受体(BCR)的信号可以驱动B细胞的激活，并有助于B细胞分化为分泌抗体的浆细胞。阳性的bcr信号被一些限制B细胞激活和浆细胞分化的膜局部抑制受体所抵消。在动物模型和人类患者中，这些负信号通路的缺陷可能导致自身抗体的产生和自身免疫性疾病。我们之前已经证明转录因子Ets1可以抑制B细胞向浆细胞的分化。在这里，我们测试了BCR和抑制受体在控制小鼠B细胞Ets1表达中的作用。我们发现，BCR或TLR信号通过依赖于PI3激酶、BTK、IKK2和JNK的途径下调了B细胞中Ets1的表达。抑制通路的缺陷，如酪氨酸激酶Lyn、磷酸酶SHP1或膜受体CD22和/或Siglec-G的缺失，导致BCR信号增强和Ets1表达下降。在Lyn或SHP1缺陷的B细胞中恢复Ets1的表达会抑制其增强的浆细胞分化。我们的发现表明，ETS1的下调是通过bcr或tlr信号途径对B细胞的激活做出反应，从而允许B细胞分化，并且维持ets1的表达是B细胞中LYN→CD22/SiglecG→SHP1抑制通路的重要功能。
Signaling through the B cell receptor (BCR) can drive B cell activation and contribute to B cell differentiation into antibody-secreting plasma cells. The positive BCR signal is counterbalanced by a number of membrane-localized inhibitory receptors that limit B cell activation and plasma cell differentiation. Deficiencies in these negative signaling pathways may cause autoantibody generation and autoimmune disease in both animal models and human patients. We have previously shown that the transcription factor Ets1 can restrain B cell differentiation into plasma cells. Here, we tested the roles of the BCR and inhibitory receptors in controlling the expression of Ets1 in mouse B cells. We found that Ets1 is down regulated in B cells by BCR or TLR signaling through a pathway dependent on PI3 kinase, Btk, IKK2 and JNK. Deficiencies in inhibitory pathways, such as a loss of the tyrosine kinase Lyn, the phosphatase SHP1 or membrane receptors CD22 and/or Siglec-G, result in enhanced BCR signaling and decreased Ets1 expression. Restoring Ets1 expression in Lyn- or SHP1-deficient B cells inhibits their enhanced plasma cell differentiation. Our findings indicate that downregulation of Ets1 occurs in response to B cell activation via either BCR or TLR signaling thereby allowing B cell differentiation and that the maintenance of Ets1 expression is an important function of the inhibitory Lyn → CD22/SiglecG → SHP1 pathway in B cells.
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