T cell responses in mammalian diaphanous-related formin mDia1 knock-out mice
T cell responses in mammalian diaphanous-related formin mDia1 knock-out mice
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DOI：
10.1074/jbc.m703243200
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发表时间：
2007-08-24
影响因子：
4.8
通讯作者：
Alberts, Arthur S.
中科院分区：
文献类型：
--
作者：
Eisenmann, Kathryn M.;West, Richard A.;Alberts, Arthur S.
活化的T细胞在T细胞受体结合或与黏附刺激相互作用时，会迅速组装丝状（F -）肌动蛋白网络，以促进细胞迁移和免疫突触的形成。分支状丝状体组装对这一过程至关重要，且依赖于肌动蛋白成核促进因子威斯科特 - 奥尔德里奇综合征蛋白（WASp）对Arp2/3复合物的激活。WAS基因的遗传破坏与造血系统恶性肿瘤和各种血细胞减少症有关。尽管WASp和Arp2/3对T细胞反应的作用已得到相当充分的表征，但哺乳动物透明蛋白（mDia）相关的成蛋白既能使无分支的F - 肌动蛋白成核又能进行持续性延伸，其作用尚未得到证实。在此，我们报告了敲除编码经典成蛋白p140mDia1的小鼠Drf1基因后对T细胞发育和功能的影响。Drf1（-/-）小鼠出现淋巴细胞减少症，其特征是淋巴组织中T细胞数量减少。与p140mDia1在肌动蛋白细胞骨架调节中的作用一致，分离的Drf1（-/-）脾T细胞对细胞外基质蛋白的黏附性差，并且对趋化刺激的迁移完全受阻。整联蛋白和趋化因子受体的表达不受Drf1（-/-）基因敲除的影响。在对增殖刺激作出反应时，胸腺和脾的Drf1（-/-）T细胞均无法增殖；活化的Drf1（-/-）T细胞中ERK1/2的激活也减弱。这些数据表明p140mDia1在体内驱动正常T细胞反应的动态细胞骨架重塑事件中起着核心作用。
Activated T cells rapidly assemble filamentous ( F-) actin networks in response to ligation of the T cell receptor or upon interaction with adhesive stimuli in order to facilitate cell migration and the formation of the immune synapse. Branched filament assembly is crucial for this process and is dependent upon activation of the Arp2/3 complex by the actin nucleation- promoting factor Wiskott-Aldrich Syndrome protein ( WASp). Genetic disruption of the WAS gene has been linked to hematopoietic malignancies and various cytopenias. Although the contributions of WASp and Arp2/3 to T cell responses are fairly well characterized, the role of the mammalian Diaphanous ( mDia)related formins, which both nucleate and processively elongate non-branched F- actin, has not been demonstrated. Here, we report the effects on T cell development and function following the knock out of the murine Drf1 gene encoding the canonical formin p140mDia1. Drf1(-/-) mice develop lymphopenia characterized by diminished T cell populations in lymphoid tissues. Consistent with a role for p140mDia1 in the regulation of the actin cytoskeleton, isolated Drf1(-/-) splenic T cells adhered poorly to extracellular matrix proteins and migration in response to chemotactic stimuli was completely abrogated. Both integrin and chemokine receptor expression was unaffected by Drf1 (-/-) targeting. In response to proliferative stimuli, both thymic and splenic Drf1 (-/-) T cells failed to proliferate; ERK1/2 activation was also diminished in activated Drf1(-/-) T cells. These data suggest a central role for p140mDia1 in vivo in dynamic cytoskeletal remodeling events driving normal T cell responses.