Ex vivo expansion of human CD8+ T cells using autologous CD4+ T cell help.
Ex vivo expansion of human CD8+ T cells using autologous CD4+ T cell help.
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DOI：
10.1371/journal.pone.0030229
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Hirano N
中科院分区：
文献类型：
--
作者：
Butler MO;Imataki O;Yamashita Y;Tanaka M;Ansén S;Berezovskaya A;Metzler G;Milstein MI;Mooney MM;Murray AP;Mano H;Nadler LM;Hirano N
利用活体小鼠模型，已深入研究了CD4+T细胞的作用机制。然而，很大程度上缺乏对人类CD4+T细胞的机制分析帮助。我们的目标是通过一种新的体外模型来阐明人类CD4+T细胞帮助CD8+T细胞增殖的机制。我们开发了一种新型的基于人类细胞的基因工程人工APC，AAPC/mOKT3，它表达了一种膜形式的抗CD3单抗OKT3以及其他免疫辅助分子。不需要增加同种异体饲养细胞，AAPC/mOKT3能够同时扩增外周T细胞和肿瘤浸润性T细胞，而不受人类白细胞抗原的限制。扩增的肿瘤浸润性淋巴细胞主要分泌Th1型细胞因子、干扰素-γ和IL-2。在这个基于AAPC的系统中，自体CD4+T细胞的存在与CD8+T细胞的体外扩增显著相关。CD4+T细胞衍生的细胞因子IL-2和IL-21是这一作用所必需的，但不是充分的。然而，通过加入IL-2/IL-21和上调CD8+T细胞上的IL-21受体，CD8+T细胞对CD8+T细胞增殖的帮助在一定程度上被重现。我们已经建立了一个体外模型，该模型借助CD8+T细胞，促进了我们对人类CD4+T细胞免疫生物学的理解。我们的数据表明，人类的CD4+T细胞可以被用来在体外扩增CD8+T细胞。
Using in vivo mouse models, the mechanisms of CD4+ T cell help have been intensively investigated. However, a mechanistic analysis of human CD4+ T cell help is largely lacking. Our goal was to elucidate the mechanisms of human CD4+ T cell help of CD8+ T cell proliferation using a novel in vitro model. We developed a genetically engineered novel human cell-based artificial APC, aAPC/mOKT3, which expresses a membranous form of the anti-CD3 monoclonal antibody OKT3 as well as other immune accessory molecules. Without requiring the addition of allogeneic feeder cells, aAPC/mOKT3 enabled the expansion of both peripheral and tumor-infiltrating T cells, regardless of HLA-restriction. Stimulation with aAPC/mOKT3 did not expand Foxp3+ regulatory T cells, and expanded tumor infiltrating lymphocytes predominantly secreted Th1-type cytokines, interferon-γ and IL-2. In this aAPC-based system, the presence of autologous CD4+ T cells was associated with significantly improved CD8+ T cell expansion in vitro. The CD4+ T cell derived cytokines IL-2 and IL-21 were necessary but not sufficient for this effect. However, CD4+ T cell help of CD8+ T cell proliferation was partially recapitulated by both adding IL-2/IL-21 and by upregulation of IL-21 receptor on CD8+ T cells. We have developed an in vitro model that advances our understanding of the immunobiology of human CD4+ T cell help of CD8+ T cells. Our data suggests that human CD4+ T cell help can be leveraged to expand CD8+ T cells in vitro.
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影响因子：
11.5
作者：
Kershaw, Michael H.;Westwood, Jennifer A.;Hwu, Patrick
通讯作者：
Hwu, Patrick
通过淋巴结消除来清除稳态细胞因子下沉，增强了采用转移的肿瘤特异性CD8+ T细胞的功效。
影响因子：
15.3
作者：
Gattinoni, Luca;Finkelstein, Steven E;Klebanoff, Christopher A;Antony, Paul A;Palmer, Douglas C;Spiess, Paul J;Hwang, Leroy N;Yu, Zhiya;Wrzesinski, Claudia;Heimann, David M;Surh, Charles D;Rosenberg, Steven A;Restifo, Nicholas P
通讯作者：
Restifo, Nicholas P
影响因子：
3.9
作者：
Dudley, ME;Wunderlich, JR;Rosenberg, SA
通讯作者：
Rosenberg, SA
影响因子：
158.5
作者：
Hunder, Naomi N.;Wallen, Herschel;Yee, Cassian
通讯作者：
Yee, Cassian
影响因子：
3.9
作者：
Huang, JP;Khong, HT;Robbins, PF
通讯作者：
Robbins, PF