Requirement of cognate CD4+ T-cell recognition for the regulation of allospecific CTL by human CD4+ CD127- CD25+ FOXP3+ cells generated in MLR.
Requirement of cognate CD4+ T-cell recognition for the regulation of allospecific CTL by human CD4+ CD127- CD25+ FOXP3+ cells generated in MLR.
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DOI：
10.1371/journal.pone.0022450
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Mathew JM
中科院分区：
文献类型：
--
作者：
Yu Y;Miller J;Leventhal JR;Tambur AR;Chandrasekaran D;Levitsky J;Luo X;Mathew JM
尽管已经描述了同种异体反应性人类 CTL 的免疫调节，但 CD4+ Tregs 对 CD8+ 细胞毒性的直接影响及其相互作用机制尚未得到很好的阐明。因此，在MLR中生成人CD4+CD127−CD25+FOXP3+ Tregs，进行免疫选择，然后使用改良的51铬释放测定（Micro-CML）、MLR和基于CFSE的多荧光染料流式细胞术增殖测定来测试它们的同种异体调节功能和相关机制。据观察，7 天的 MLR 后，CD4+CD127−CD25+FOXP3+ 细胞的数量增加。对 CD4+CD127−CD25+ 细胞进行免疫选择后，将它们指定为 MLR-Treg。当作为第三组分调节剂添加时，MLR-Tregs 以浓度依赖性方式抑制自体 PBMC 的同种反应性增殖。该抑制是准抗原特异性的，因为在较高MLR-Treg调节剂剂量下该抑制是非特异性的，但非特异性随着较低剂量而消失，此时特异性抑制仍然显着。当在 micro-CML 测定中进行测试时，PBMC 和纯化的 CD8+ 应答者发生 CTL 抑制。然而，仅在未纯化的 PBMC 应答者中观察到 CTL 抑制的抗原特异性，而在纯化的 CD8+ 应答者中或什至在 CD8+ 应答者加非 T“APC” 中未观察到 CTL 抑制的抗原特异性。然而，当将自体纯化的 CD4+ T 细胞添加到 CD8+ 应答者中时，CTL 调节的同种异体特异性得以恢复。无论存在或不存在 IL-2，MLR-Treg 都会抑制 CD8+ 细胞的增殖。 MLR-Tregs 的抑制是通过下调响应 CD8+ 细胞上的细胞内穿孔素、颗粒酶 B 和膜结合 CD25 分子来介导的。因此，得出结论，人 CD4+CD127−CD25+FOXP3+ MLR-Tregs 下调同种异体细胞毒性反应。然而，调节同种异体特异性需要存在同源响应 CD4+ T 细胞。 CD8+ CTL 调节机制包括增殖受损、溶细胞分子和 CD25+ 激活表位表达减少。
Although immunoregulation of alloreactive human CTLs has been described, the direct influence of CD4+ Tregs on CD8+ cytotoxicity and the interactive mechanisms have not been well clarified. Therefore, human CD4+CD127−CD25+FOXP3+ Tregs were generated in MLR, immunoselected and their allospecific regulatory functions and associated mechanisms were then tested using modified 51Chromium release assays (Micro-CML), MLRs and CFSE-based multi-fluorochrome flow cytometry proliferation assays. It was observed that increased numbers of CD4+CD127−CD25+FOXP3+ cells were generated after a 7 day MLR. After immunoselection for CD4+CD127−CD25+ cells, they were designated as MLR-Tregs. When added as third component modulators, MLR-Tregs inhibited the alloreactive proliferation of autologous PBMC in a concentration dependent manner. The inhibition was quasi-antigen specific, in that the inhibition was non-specific at higher MLR-Treg modulator doses, but non-specificity disappeared with lower numbers at which specific inhibition was still significant. When tested in micro-CML assays CTL inhibition occurred with PBMC and purified CD8+ responders. However, antigen specificity of CTL inhibition was observed only with unpurified PBMC responders and not with purified CD8+ responders or even with CD8+ responders plus Non-T “APC”. However, allospecificity of CTL regulation was restored when autologous purified CD4+ T cells were added to the CD8+ responders. Proliferation of CD8+ cells was suppressed by MLR-Tregs in the presence or absence of IL-2. Inhibition by MLR-Tregs was mediated through down-regulation of intracellular perforin, granzyme B and membrane-bound CD25 molecules on the responding CD8+ cells. Therefore, it was concluded that human CD4+CD127−CD25+FOXP3+ MLR-Tregs down-regulate alloreactive cytotoxic responses. Regulatory allospecificity, however, requires the presence of cognate responding CD4+ T cells. CD8+ CTL regulatory mechanisms include impaired proliferation, reduced expression of cytolytic molecules and CD25+ activation epitopes.
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影响因子：
32.4
作者：
Mempel, Thorsten R.;Pittet, Mikael J.;von Andrian, Ulrich H.
通讯作者：
von Andrian, Ulrich H.
DOI：
10.1073/pnas.0408197102
发表时间：
2005-01-11
影响因子：
11.1
作者：
Chen, ML;Pittet, MJ;Khazaie, K
通讯作者：
Khazaie, K
影响因子：
5.8
作者：
Cobbold, Stephen P
通讯作者：
Cobbold, Stephen P
影响因子：
5.4
作者：
Miqueu, Patrick;Degauque, Nicolas;Brouard, Sophie
通讯作者：
Brouard, Sophie
DOI：
10.1016/j.trre.2010.04.002
发表时间：
2010-07
期刊：
Transplantation reviews (Orlando, Fla.)
影响因子：
--
作者：
Gorantla VS;Schneeberger S;Brandacher G;Sucher R;Zhang D;Lee WP;Zheng XX
通讯作者：
Zheng XX