Shp1 signalling is required to establish the long-lived bone marrow plasma cell pool.
Shp1 signalling is required to establish the long-lived bone marrow plasma cell pool.
复制标题
DOI：
10.1038/ncomms5273
复制
发表时间：
2014-06-30
影响因子：
16.6
通讯作者：
Lam, Kong-Peng
中科院分区：
文献类型：
--
作者：
Li, Yan-Feng;Xu, Shengli;Ou, Xijun;Lam, Kong-Peng
编码SHP1蛋白酪氨酸磷酸酶的Ptpn6基因的生殖系或B细胞特异性缺失会导致扭曲的B淋巴细胞生成和系统自身免疫。在这里，为了研究其在B细胞终末分化中的作用，我们建立了仅在激活的B细胞中去除SHP1的Ptpn6f/fAicdaCre/+小鼠。我们发现，Ptpn6f/fAicdaCre/+小鼠具有正常的B细胞发育，但对T细胞依赖的抗原表现出缺陷的类别转换初级抗体反应和召回抗体反应。生发中心存在，但不存在，也不形成记忆B细胞。有趣的是，SHP1缺陷的浆细胞在脾中产生，但并不对骨髓长寿池做出贡献。缺乏SHP1的浆细胞表现出异常的α-4-β-1整合素活化，这是由于src-和pI3-激酶信号的失调，并在体外表现出减弱的迁移和体内重组时的缺陷骨髓归巢。中断α4β1-VCAM-1的相互作用可纠正这一缺陷。这些数据表明，SHP1信号是建立终生保护性体液免疫所必需的。SHP-1信号通路是B淋巴细胞正常发育所必需的，但其在B淋巴细胞终末分化中的作用尚未完全确定。在这里，作者表明，由于异常的整合素激活，SHP-1消融损害了长期驻留在骨髓中的浆细胞的建立。
Germline or B-cell-specific loss of Ptpn6 gene encoding the Shp1 protein tyrosine phosphatase leads to skewed B lymphopoiesis and systemic autoimmunity. Here, to study its role in B-cell terminal differentiation, we generated Ptpn6f/fAicdaCre/+ mice with Shp1 ablated only in activated B cells. We show that Ptpn6f/fAicdaCre/+ mice have normal B-cell development but exhibit defective class-switched primary and recalled antibody response to a T-cell-dependent antigen. Germinal centres are present but do not persist and memory B cells are not formed. Interestingly, Shp1-deficient plasma cells are generated in the spleen but do not contribute to the bone marrow long-lived pool. Plasma cells lacking Shp1 exhibit aberrant α4β1 integrin activation due to dysregulated Src- and PI3-kinase signalling and manifest attenuated migration in vitro and defective bone marrow homing when reconstituted in vivo. Interrupting α4β1–VCAM-1 interaction rectifies this defect. These data suggest that Shp1 signalling is required for the establishment of a life-long protective humoral immunity. SHP-1 signalling is required for the normal development of B lymphocytes but its role in the terminal differentiation of these cells has not been fully established. Here, the authors show that SHP-1 ablation impairs the establishment of long-lived bone marrow-resident plasma cells due to aberrant integrin activation.
登录
查看更多内容
DOI：
10.1126/science.1213368
发表时间：
2012-06-01
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Khalil AM;Cambier JC;Shlomchik MJ
通讯作者：
Shlomchik MJ
影响因子：
8.7
作者：
Lorenz U
通讯作者：
Lorenz U
DOI：
10.1084/jem.194.1.45
发表时间：
2001-07-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hargreaves DC;Hyman PL;Lu TT;Ngo VN;Bidgol A;Suzuki G;Zou YR;Littman DR;Cyster JG
通讯作者：
Cyster JG
影响因子：
20.3
作者：
Imai, Yoichi;Park, Eun Jeong;Shimaoka, Motomu
通讯作者：
Shimaoka, Motomu
影响因子：
32.4
作者：
CYSTER, JG;GOODNOW, CC
通讯作者：
GOODNOW, CC