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Molecular mechanisms of proliferation and differentiation of germinal center B cells

生发中心B细胞增殖分化的分子机制

基本信息

批准号：
09470091
负责人：
TAKATSU Kiyoshi
金额：
$ 8.51万
依托单位：
The University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470091/
关键词：
IL-5 B cell differentiation CD40 CD38 IL-4 Btk X-linked immunodeficiency Follicular mantle zone メモリーB細胞胚中心 B細胞超変異抗体の親和性 CD40とリガンドサイトカイン

项目摘要

Germinal center (GC) develops in secondary lymphoid tissues in response to thymus-dependent (TD) antigens (Ag). To investigate the molecular mechanism of mouse GC B cell differentiation and elucidate the function of GC B cells from X-linked immunodeficient(Xid)mice, we enriched GC B cells from spleen of TD Ag-immunized mice, monitored the expression of functional molecules, and determined the differentiation into Ag-specific IgGI antibody forming cells (AFCs) in response to anti-CD40 mAb and cytokines in vitro. GC B cells expressed IL-4 receptor (R), and approximately 5% of GC B cells expressed IL-5R.IL-4 in the presence of anti-CD40 mAb induced the differentiation of GC B cells from wild-type mice into Ag-specific IgGI AFCs, and enhanced the IL-5R expression on GC B cells from wild-type mice. IL-5 enhanced further the IgGI AFC response. The GC B cells from Xid mice responded to anti-CD40 mAb and IL-4 resulting in the IgGI response, whereas IL-5 did not enhance the response. These findings suggest that anti-CD40 mAb, IL-4, and IL-5 play a critical role in differentiation of mouse GC B cells. The GCB cells from Xid mice show functional defect with respect to IL-5-mediated differentiation.We then examined effect of CD40 and CD38 on differentiation of GC and follicular mantle(FM)B cells. The results showed that IL-5Ralpha positive cells were mainly distributed in GC which also expressed CD40, whereas CD38 expression was down-regulated on GC B cells. Stimulation of GC B cells with IL-5 plus anti-CD38 mAb did not induce the IgGI response. The expression of IL-5Ralpha, CD38, and CD40 in Xidmice was similar to that in wild-type mice. Furthermore, IL-5Ralpha deficient mice showed normal response to TD Ag, regarding GC development and Ag-specific IgGI production. These results suggest that IL-5 plays a critical role in differentiation of mouse GC B cells as a costimulatory factor rather than an essential factor.

胸腺依赖性抗原（Ag）在次级淋巴组织中产生Germinal Center（GC）。为探讨X-连锁免疫缺陷（Xid）小鼠GC B细胞分化的分子机制，阐明GC B细胞的功能，我们从TD Ag免疫小鼠脾脏中富集GC B细胞，检测其功能分子的表达，并在体外检测抗CD 40单克隆抗体和细胞因子诱导下向Ag特异性IgGI抗体形成细胞（AFC）的分化。GC B细胞表达IL-4受体（R），约5%的GC B细胞表达IL-5 R。IL-4在抗CD 40 mAb存在下诱导野生型小鼠GC B细胞分化为Ag特异性IgGI AFC，并增强野生型小鼠GC B细胞上IL-5 R的表达。IL-5进一步增强IgGI AFC应答。来自Xid小鼠的GC B细胞对抗CD 40 mAb和IL-4产生应答，导致IgGI应答，而IL-5不增强应答。这些结果表明，抗CD 40 mAb，IL-4，IL-5在小鼠GC B细胞的分化中起着关键作用。本研究以Xid小鼠GCB细胞为研究对象，观察了CD 40和CD 38对IL-5介导的GCB细胞向GC和滤泡套（follicular mantle，FM）B细胞分化的影响。结果表明，IL-5 R α阳性细胞主要分布于GC，GC同时表达CD 40，而CD 38在GC B细胞表达下调。用IL-5加抗CD 38 mAb刺激GC B细胞未诱导IgGI应答。Xid小鼠中IL-5 R α、CD 38和CD 40的表达与野生型小鼠相似。此外，IL-5 R α缺陷小鼠对TD Ag表现出正常反应，关于GC发展和Ag特异性IgGI产生。这些结果表明，IL-5在小鼠GC B细胞的分化中起关键作用，作为一个共刺激因子，而不是一个必需的因素。