CXCR4 Expression on Activated B Cells Is Downregulated by CD63 and IL-21
CXCR4 Expression on Activated B Cells Is Downregulated by CD63 and IL-21
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DOI：
10.4049/jimmunol.1003401
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发表时间：
2011-03
期刊：
影响因子：
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通讯作者：
N. Yoshida;Daisuke Kitayama;M. Arima;A. Sakamoto;A. Inamine;H. Watanabe-Takano;M. Hatano;T. Koike;T. Tokuhisa
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文献类型：
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作者：
N. Yoshida;Daisuke Kitayama;M. Arima;A. Sakamoto;A. Inamine;H. Watanabe-Takano;M. Hatano;T. Koike;T. Tokuhisa
CXCR4的表达对中心母细胞在生发中心(GCs)暗区的定位至关重要，中心细胞下调CXCR4，从而离开暗区驻留在亮区。然而，调控CXCR4下调中心细胞的机制尚不清楚。在这项研究中，我们发现中心母细胞内的CXCR4的数量与中心细胞中的CXCR4的数量相似，这表明CXCR4蛋白在这些GC B细胞中的表达受到不同的控制。T滤泡辅助细胞产生的主要细胞因子IL-21重新刺激活化的B细胞，通过诱导与内吞相关的GRK6表达来加速CXCR4的内化。尽管IL-21刺激下调了GC B细胞上CXCR4的表达，但在IL-21R缺陷小鼠的脾中出现了CXCR4低中心细胞，这表明了下调的其他机制。CD63(将CXCR4募集到CD4T细胞中的晚期内体)在中心细胞中的水平高于中心母细胞，在活化的Bcl6缺陷的B细胞中显著升高。在静息B细胞CD63基因染色质上检测到转录抑制因子Bcl6，因此CD63是Bcl6的分子靶点。小干扰RNA下调活化的Bcl6缺陷B细胞CD63基因表达上调B细胞表面CXCR4的表达。此外，在活化的B细胞培养中加入Bcl6抑制剂可增加活化B细胞中CD63mRNA的表达，并下调其上CXCR4的表达。因此，CXCR4可以通过IL-21诱导的内吞作用和CD63介导的内体募集作用下调活化的B细胞，这些机制可能有助于下调CXCR4对中心细胞的调控。
CXCR4 expression is critical for localization of centroblasts in the dark zone of germinal centers (GCs), and centrocytes downregulate CXCR4 and thus leave the dark zone to reside in the light zone. However, mechanisms governing CXCR4 downregulation on centrocytes are not known. In this study, we show that the amount of intracellular CXCR4 in centroblasts was similar to that in centrocytes, suggesting differential control of CXCR4 protein expression in these GC B cells. Restimulation of activated B cells with IL-21, which is a major cytokine produced by T follicular helper cells, accelerated CXCR4 internalization by inducing endocytosis-related GRK6 expression. Although CXCR4 expression was downregulated on GC B cells by IL-21 stimulation, CXCR4low centrocytes developed in the spleens of IL-21R–deficient mice, suggesting other mechanisms for downregulation. The level of CD63 (which recruits CXCR4 to late endosome in CD4 T cells) in centrocytes was more than that in centroblasts and was strikingly elevated in activated Bcl6-deficient B cells. Bcl6, a transcriptional repressor, was detected on the chromatin of the CD63 gene in resting B cells, therefore CD63 is a molecular target of Bcl6. Downregulation of CD63 mRNA in activated Bcl6-deficient B cells by small interfering RNA upregulated CXCR4 expression on the B cells. Furthermore, addition of Bcl6 inhibitor to activated B cell cultures increased CD63 mRNA expression in (and downregulated CXCR4 expression on) those activated B cells. Thus, CXCR4 can be downregulated on activated B cells by IL-21–induced endocytosis and CD63-mediated endosomal recruitment, and these mechanisms may contribute to downregulation of CXCR4 on centrocytes.