CD19 signaling is impaired in murine peritoneal and splenic B-1 B lymphocytes
CD19 signaling is impaired in murine peritoneal and splenic B-1 B lymphocytes
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DOI：
10.1016/j.molimm.2009.04.015
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发表时间：
2009-08-01
影响因子：
3.6
通讯作者：
Bondada, Subbarao
中科院分区：
文献类型：
--
作者：
Dasu, Trivikram;Sindhava, Vishal;Bondada, Subbarao
B-1细胞主要存在于体腔、扁桃体、派伊尔集合淋巴结、脾脏（一小部分-类似于5%）中，并且在淋巴结中不存在。它们是体内天然IgM的主要来源。B-1细胞表达多反应性B细胞受体（BCR），其与自身抗原交叉反应，因此与自身免疫疾病有关。以前，我们报道腹膜B-1细胞缺乏CD 19介导的细胞内信号，导致Ca 2+动员。在这里，我们发现，脾B-1细胞，像腹膜B-1细胞，是有缺陷的钙释放后，B细胞激活共交联BCR和CD 19。在没有细胞外Ca 2+来源的情况下，B-1和B-2细胞之间的细胞内Ca 2+通量相似。此外，在B细胞的两个亚群中的Ca 2+释放的细胞内组分主要是PI 3 K依赖性的。BCR和CD 19共交联激活Akt，Akt是脾B-2细胞中PI 3 K下游存活和增殖信号的关键介导物。另一方面，脾B-1细胞在类似处理后不磷酸化Akt（S473）。此外，BCR+ CD 19交联诱导的JNK磷酸化在脾B-1细胞中大大减少。相反，B-1细胞表现出增加的组成型活性pLyn水平，其似乎具有抑制作用。用Src激酶特异性抑制剂部分抑制pLyn可恢复CD 19诱导的Ca ~（2+）反应和BCR诱导的增殖反应。这些发现表明，腹膜和脾B-1 B淋巴细胞中的CD 19介导的信号缺陷，这部分是由于组成性活性林恩的水平较高。(C)2009爱思唯尔有限公司保留所有权利。
B-1 cells reside predominantly within the coelomic cavities, tonsils, Peyer's patches, spleen (a minor fraction - similar to 5%) and are absent in the lymph nodes. They are the primary sources of natural IgM in the body. B-1 cells express polyreactive B cell receptors (BCRs) that cross react with self-antigens and are thus implicated in auto-immune disorders. Previously, we reported that peritoneal B-1 cells are deficient in CD19-mediated intracellular signals leading to Ca2+ mobilization. Here, we find that splenic B-1 cells, like peritoneal B-1 cells, are defective in Ca2+ release upon B cell activation by co-cross-linking BCR and CD19. in the absence of extracellular sources of Ca2+, intracellular Ca2+ flux is similar between B-1 and B-2 cells. Moreover, the intracellular component of Ca2+ release in both subsets of B cells is mostly PI3K dependent. BCR and CD19 co-cross-linking activates Akt, a key mediator of survival and proliferation signals downstream of PI3K in splenic B-2 cells. Splenic B-1 cells, on the other hand, do not phosphorylate Akt (S473) upon similar treatment. Furthermore, BCR+CD19 cross-linking induced phosphorylation of JNK is much reduced in splenic B-1 cells. In contrast, B-1 cells exhibited increased levels of constitutively active pLyn which appears to have an inhibitory role. The CD19 induced Ca2+ response and BCR induced proliferation response were restored by a partial inhibition of pLyn with Src kinase specific inhibitors. These findings suggest a defect in CD19-mediated signals in both peritoneal and splenic B-1 B lymphocytes, which is in part, due to higher levels of constitutively active Lyn. (C) 2009 Elsevier Ltd. All rights reserved.