Downregulation of RhoA and changes in T cell cytoskeleton correlate with the abrogation of allograft rejection.
Downregulation of RhoA and changes in T cell cytoskeleton correlate with the abrogation of allograft rejection.
复制标题
DOI：
10.1016/j.trim.2010.06.009
复制
发表时间：
2010-08
影响因子：
1.5
通讯作者：
Ghobrial RM
中科院分区：
文献类型：
--
作者：
Skelton TS;Tejpal N;Gong Y;Kloc M;Ghobrial RM
适当的肌动蛋白细胞骨架结构和动力学是必不可少的免疫反应中的事件，如T细胞迁移，T细胞受体的重新分布，并与抗原呈递细胞的相互作用。因此，T细胞活化、下游信号传导事件和效应器功能都是肌动蛋白依赖性的。肌动蛋白细胞骨架的结构和动力学的调节蛋白属于超家族的小GTP结合蛋白，如RhoA GTP酶。我们以前的研究表明，给予一种MHC I类异源嵌合分子[α 1h 1/u]-RT1.Aa，它含有供体型（Wistar Furth，WF; RT 1u）免疫原性表位（ACI，RT 1a）序列，对异位WF心脏的ACI受体，导致TCR库的限制，T细胞浸润到异位心脏同种异体移植物中的抑制，消除急性和慢性排斥反应，诱导同种异体移植物的无限期存活。在这里，我们表明，异源嵌合分子治疗引起下调RhoA GT3在T细胞。这导致肌动蛋白和肌动蛋白结合蛋白Hip 55在这些细胞中的分布发生了巨大变化，这反过来又抑制了T细胞向移植物中的浸润。这表明同种异体嵌合分子的免疫抑制活性是通过下调RhoA途径和破坏T细胞肌动蛋白细胞骨架的适当组织以抑制T细胞功能如运动性和/或TCR信号传导事件来实现的。
Proper actin cytoskeleton architecture and dynamics are indispensable for events in the immunological response such as T cell migration, redistribution of T cell receptors, and interaction with antigen presenting cells. Thus, T cell activation, downstream signaling events and effector functions are all actin-dependent. Actin cytoskeleton architecture and dynamics are regulated by proteins belonging to the superfamily of small GTP-binding proteins, such as RhoA GTPase. We previously showed that the administration of an MHC class I allochimeric molecule [α1h1/u]-RT1.Aa, which contains donor-type (Wistar Furth, WF; RT1u) immunogenic epitopes displayed on recipient-type (ACI, RT1a) sequences, to the ACI recipient of heterotopic WF heart resulted in the restriction of the TCR repertoire, inhibition of T cell infiltration into the heterotopic cardiac allografts, abrogation of acute and chronic rejection, and induction of indefinite survival of the allograft. Here we show that the allochimeric molecule treatment caused down regulation of RhoA GTPase in T cells. This resulted in dramatic changes in the distribution of actin and the actin-binding protein, Hip55, in these cells, which in turn, inhibited T cell infiltration into the graft. This indicates that the immunosuppressive activity of the allochimeric molecule is achieved via downregulation of the RhoA pathway and disruption of the proper organization of T cell actin cytoskeleton to inhibit T cell functions such as motility and/or TCR signaling events.
登录
查看更多内容
影响因子：
5.4
作者：
Brossard, C;Feuillet, V;Trautmann, A
通讯作者：
Trautmann, A
影响因子：
4.4
作者：
Tharaux, PL;Bukoski, RC;Coffman, TM
通讯作者：
Coffman, TM
影响因子：
5.3
作者：
Han, J;Shui, JW;Tan, TH
通讯作者：
Tan, TH
影响因子：
3.7
作者：
Liu, Dahai;Shen, Xiu-Da;Ghobrial, Rafik M.
通讯作者：
Ghobrial, Rafik M.
影响因子：
6.2
作者：
Semiletova, NV;Shen, XD;Ghobrial, RM
通讯作者：
Ghobrial, RM