Li Yan-Feng, Xu Shengli, Ou Xijun, Lam Kong-Peng
Immunology Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore.
1] Immunology Group, Bioprocessing Technology Institute, Agency for Science, Technology and Research, Singapore 138668, Singapore [2] Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117599, Singapore.
Nat Commun. 2014 Jun 30;5:4273. doi: 10.1038/ncomms5273.
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 Ptpn6(f/f)Aicda(Cre/+) mice with Shp1 ablated only in activated B cells. We show that Ptpn6(f/f)Aicda(Cre/+) 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.
编码Shp1蛋白酪氨酸磷酸酶的Ptpn6基因的种系或B细胞特异性缺失会导致B淋巴细胞生成异常和全身性自身免疫。在此，为了研究其在B细胞终末分化中的作用，我们构建了仅在活化B细胞中敲除Shp1的Ptpn6(f/f)Aicda(Cre/+)小鼠。我们发现，Ptpn6(f/f)Aicda(Cre/+)小鼠的B细胞发育正常，但对T细胞依赖性抗原的类别转换初级和回忆性抗体反应存在缺陷。生发中心存在但不能持续存在，记忆B细胞未形成。有趣的是，脾脏中产生了缺乏Shp1的浆细胞，但它们对骨髓长寿池没有贡献。缺乏Shp1的浆细胞由于Src和PI3激酶信号失调而表现出异常的α4β1整合素激活，在体外表现出迁移减弱，在体内重建时表现出骨髓归巢缺陷。阻断α4β1-VCAM-1相互作用可纠正这一缺陷。这些数据表明，Shp1信号对于建立终身保护性体液免疫是必需的。
