TCR stimulation without co-stimulatory signals induces expression of "tolerogenic" genes in memory CD4 T cells but does not compromise cell proliferation.
TCR stimulation without co-stimulatory signals induces expression of "tolerogenic" genes in memory CD4 T cells but does not compromise cell proliferation.
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DOI：
10.1016/j.molimm.2014.09.013
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发表时间：
2015-02
影响因子：
3.6
通讯作者：
A. Xie;Xiong Zheng;M. Khattar;P. Schroder;S. Stepkowski;J. Xia;Wenhao Chen
中科院分区：
文献类型：
--
作者：
A. Xie;Xiong Zheng;M. Khattar;P. Schroder;S. Stepkowski;J. Xia;Wenhao Chen
记忆T细胞抵抗共刺激阻断，并在移植和自身免疫性疾病中提出了独特的治疗挑战。在此，我们确定了记忆T细胞是否比幼稚T细胞表达更少的"致耐受性"基因，以在共刺激信号剥夺下加强增殖反应。因此，在没有共刺激的体外TCR刺激期间评估了记忆和幼稚CD4 + T细胞中CD40致耐受性基因的表达。简言之，在用单独的抗CD3 mAb刺激TCR后，记忆性CD4 + T细胞表现出比幼稚CD4 + T细胞更多的增殖。令人惊讶的是，在抗CD3 mAb刺激后24 h，记忆性CD4 + T细胞表达的转录因子Egr 2水平比幼稚T细胞高5倍以上，跨膜E3泛素连接酶GRAIL水平比幼稚T细胞高20倍。因此，致耐受性基因Egr 2和GRAIL在记忆性CD4 + T细胞中的高水平表达不会阻止细胞增殖。重要的是，抗CD3 mAb刺激的记忆性CD4 + T细胞表达高蛋白/基因水平的磷酸化STAT5、Nedd4、Bcl-2和Bcl-XL。因此，记忆性CD4 + T细胞的共刺激非依赖性增殖可能是由于支持细胞增殖和存活的分子表达升高，而不是缺乏致耐受性分子。
Memory T cells resist co-stimulatory blockade and present a unique therapeutic challenge in transplantation and autoimmune diseases. Herein, we determined whether memory T cells express less “tolerogenic” genes than naïve T cells to reinforce a proliferative response under the deprivation of co-stimulatory signals. The expression of ∼40 tolerogenic genes in memory and naïve CD4+T cells was thus assessed during an in vitro TCR stimulation without co-stimulation. Briefly, upon TCR stimulation with an anti-CD3 mAb alone, memory CD4+T cells exhibited more proliferation than naïve CD4+T cells. To our surprise, at 24 h upon anti-CD3 mAb stimulation, memory CD4+T cells expressed more than a 5-fold higher level of the transcription factor Egr2 and a 20-fold higher level of the transmembrane E3 ubiquitin ligase GRAIL than those in naïve T cells. Hence, the high-level expression of tolerogenic genes, Egr2 and GRAIL, in memory CD4+T cells does not prevent cell proliferation. Importantly, anti-CD3 mAb-stimulated memory CD4+T cells expressed high protein/gene levels of phosphorylated STAT5, Nedd4, Bcl-2, and Bcl-XL. Therefore, co-stimulation-independent proliferation of memory CD4+T cells may be due to elevated expression of molecules that support cell proliferation and survival, but not lack of tolerogenic molecules.