RasGRP1 and RasGRP3 regulate B cell proliferation by facilitating B cell receptor-Ras signaling
RasGRP1 and RasGRP3 regulate B cell proliferation by facilitating B cell receptor-Ras signaling
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DOI：
10.4049/jimmunol.175.11.7179
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发表时间：
2005-12-01
影响因子：
4.4
通讯作者：
Stone, JC
中科院分区：
文献类型：
--
作者：
Coughlin, JJ;Stang, SL;Stone, JC
RasGRP 是 Ras 激活剂家族，具有二酰基甘油结合 C1 结构域。在 T 细胞中，RasGRP1 将 TCR 信号传导与 Ras 连接起来。 B 细胞共表达 RasGRP1 和 RasGRP3。使用 Rasgrp1 和 Rasgrp3 单无效和双无效突变小鼠，我们分析了这些蛋白在向 B 细胞中 Ras 和 Erk 发出信号中的作用。 RasGRP1 和 RasGRP3 均有助于 BCR 诱导的 Ras 激活，尽管 RasGRP3 单独负责维持未刺激细胞中的基础 Ras-GTP 水平。令人惊讶的是，RasGRP 介导的 Ras 激活对于 B 细胞发育并不是必需的，因为该过程通常发生在双突变小鼠中。然而，RasGRP 缺陷小鼠确实表现出不道德缺陷。 RasGRP3 的缺失导致免疫幼鼠中 Ab 诱导的同种型特异性缺陷。正如之前报道的，老年 Rasgrp1(-/-) 小鼠由于 T 细胞缺陷而出现脾肿大和抗核抗体。我们发现这些小鼠的几种同种型血清 Ig 水平升高。相反，Rasgrp3(-/-) 小鼠表现出低丙种球蛋白血症，并且没有表现出脾肿大或自身免疫的迹象。双突变小鼠表现出中等血清抗体滴度，尽管高于野生型小鼠。值得注意的是，双突变小鼠没有表现出自身免疫或脾肿大的迹象。发现通过使用或不使用 IL-4 的 BCR 连接诱导的 B 细胞增殖是 RasGRPI 和 RasGRP3 依赖性的。然而，RasGRP 本身并不是 B 细胞增殖所必需的，因为 LPS 诱导的增殖在双突变小鼠中不受影响。
The RasGRPs are a family of Ras activators that possess diacylglycerol-binding C1 domains. In T cells, RasGRP1 links TCR signaling to Ras. B cells coexpress RasGRP1 and RasGRP3. Using-Rasgrp1 and Rasgrp3 single and double null mutant mice, we analyzed the role of these proteins in signaling to Ras and Erk in B cells. RasGRP1 and RasGRP3 both contribute to BCR-induced Ras activation, although RasGRP3 alone is responsible for maintaining basal Ras-GTP levels in unstimulated cells. Surprisingly, RasGRP-mediated Ras activation is not essential for B cell development because this process occurs normally in double-mutant mice. However, RasGRP-deficient mice do exhibit Immoral defects. Loss of RasGRP3 led to isotype-specific deficiencies in Ab induction in immunized young mice. As reported previously, older Rasgrp1(-/-) mice develop splenomegaly and antinuclear Abs as a result of a T cell defect. We find that such mice have elevated serum Ig levels of several isotypes. In contrast, Rasgrp3(-/-) mice exhibit hypogammaglobulinemia and show no signs of splenomegaly or autoimmunity. Double-mutant mice exhibit intermediate serum Ab titers, albeit higher than wild-type mice. Remarkably, double-mutant mice exhibit no signs of autoimmunity or splenomegaly. B cell proliferation induced by BCR ligation with or without IL-4 was found to be RasGRPI- and RasGRP3-dependent. However, the RasGRPs are not required for B cell proliferation per se, because LPS-induced proliferation is unaffected in double-mutant mice.