The E3 ubiquitin ligase Cbl-b regulates expansion but not functional activity of self-reactive CD4 T cells.
The E3 ubiquitin ligase Cbl-b regulates expansion but not functional activity of self-reactive CD4 T cells.
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DOI：
10.4049/jimmunol.0901243
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发表时间：
2009-10-15
期刊：
影响因子：
--
通讯作者：
Adler AJ
中科院分区：
文献类型：
--
作者：
St Rose MC;Qui HZ;Bandyopadhyay S;Mihalyo MA;Hagymasi AT;Clark RB;Adler AJ
Cbl-b是E3泛素连接酶，其通过靶向TCR诱导的信号分子来限制T细胞中的Ag反应性。因此，Cbl-b缺乏使T细胞对抗原刺激反应过度，并使个体容易发生自身免疫。部分原因是Cbl-b−/− T细胞不需要CD 28共刺激来激活，而不充分的共刺激是导致无反应性诱导超过效应分化的关键参数，因此假设Cbl-b−/− T细胞对无反应性具有抗性。这种可能性已经在模型中得到了支持，在这些模型中，无反应性通常是在体外诱导的，或者在体内暴露于可溶性Ag团注后诱导的。在目前的研究中，我们表征了Cbl-b−/− CD 4 T细胞在体内系统中的反应，在该系统中，无反应性通常由组成性表达的外周自身抗原诱导。在自身抗原诱导的无反应性野生型CD 4 T细胞中，Cbl-b表达增加，与野生型对应物相比，Cbl-b−/− CD 4 T细胞在最初遇到同源自身抗原时经历了更稳健的增殖和扩增。然而，野生型和Cbl-b−/− CD 4 T细胞最终都对抗原再刺激产生了相同的受损反应能力。然而，在无反应性的初始诱导过程中发生的更广泛的扩增确实允许无反应性的CD 4 T细胞在用相同Ag的病毒形式替换耐受性自身Ag的初始来源后功能性复苏时扩增到更大的数量。
Cbl-b is an E3 ubiquitin ligase that limits Ag responsiveness in T cells by targeting TCR-inducible signaling molecules. Cbl-b deficiency thus renders T cells hyperresponsive to antigenic stimulation and predisposes individuals toward developing autoimmunity. In part because Cbl-b−/− T cells do not require CD28 costimulation to become activated, and insufficient costimulation is a critical parameter that confers anergy induction over effector differentiation, it has been hypothesized that Cbl-b−/− T cells are resistant to anergy. This possibility has been supported in models in which anergy is normally induced in vitro, or in vivo following exposure to soluble Ag boluses. In the current study, we characterized the response of Cbl-b−/− CD4 T cells in an in vivo system in which anergy is normally induced by a constitutively expressed peripheral self-Ag. Cbl-b expression increased in self-Ag-induced anergic wild-type CD4 T cells, and Cbl-b−/− CD4 T cells underwent more robust proliferation and expansion upon initially encountering cognate self-Ag compared with wild-type counterparts. Nevertheless, both wild-type and Cbl-b−/− CD4 T cells ultimately developed the same impaired ability to respond to antigenic restimulation. The more extensive expansion that occurred during the initial induction of anergy did, however, allow the anergic CD4 T cells to expand to greater numbers when they were functionally resuscitated following replacement of the initial source of tolerizing self-Ag with a viral form of the same Ag.
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DOI：
10.1084/jem.187.10.1555
发表时间：
1998-05-18
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Adler AJ;Marsh DW;Yochum GS;Guzzo JL;Nigam A;Nelson WG;Pardoll DM
通讯作者：
Pardoll DM
影响因子：
15.3
作者：
Apostolou, I;von Boehmer, H
通讯作者：
von Boehmer, H
DOI：
10.1084/jem.194.6.769
发表时间：
2001-09-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hawiger D;Inaba K;Dorsett Y;Guo M;Mahnke K;Rivera M;Ravetch JV;Steinman RM;Nussenzweig MC
通讯作者：
Nussenzweig MC
影响因子：
32.4
作者：
Jeon, MS;Atfield, A;Penninger, JM
通讯作者：
Penninger, JM
影响因子：
56.9
作者：
Anderson, MS;Venanzi, ES;Mathis, D
通讯作者：
Mathis, D