Ex vivo expansion of dendritic-cell-activated antigen-specific CD4+ T cells with anti-CD3/CD28, interleukin-7, and interleukin-15:: Potential for adoptive T cell immunotherapy
Ex vivo expansion of dendritic-cell-activated antigen-specific CD4+ T cells with anti-CD3/CD28, interleukin-7, and interleukin-15:: Potential for adoptive T cell immunotherapy
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DOI：
10.1016/j.clim.2005.11.003
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发表时间：
2006-04-01
影响因子：
8.6
通讯作者：
Lin, CM
中科院分区：
文献类型：
--
作者：
Chen, HW;Liao, CH;Lin, CM
越来越多的人认识到，自体环境中细胞毒性T淋巴细胞过继治疗的失败，至少部分是由于缺乏抗原特异性CD 4（+）T细胞的帮助。为了将这些细胞并入该治疗策略中，尚不知道目前使用的离体培养条件是否足以扩增和绘制具有最佳体内活性所需质量的这些T细胞。在这项研究中，我们表明，刺激与激动性抗体CD 3 + CD 28（抗CD 3/CD 28），一种常用的方法，CD 4（+）T细胞扩增，是不能扩大树突状细胞激活的B型肝炎病毒（HBV）特异性CD 4（+）T细胞的临床相关数量。然而，与白细胞介素（IL）-7和IL-15组合，它导致HBV特异性CD 4（+）T细胞在2周内扩增4000倍。该结果与IL-7和IL-15的抗凋亡作用相关。重要的是，抗原特异性在扩增过程中得以保留。虽然IL-2在抗CD 3/CD 28扩增培养物中的后期加入也导致了稳健的扩增，但与IL-7和IL-15中扩增的细胞相比，这种扩增条件使HBV特异性CD 4（+）T细胞对细胞因子撤回、活化和转化生长因子β诱导的细胞死亡更敏感。此外，NKG 2D而不是4-1BB（其配体在肿瘤细胞上组成型表达）在IL-7/IL-15扩增的HBV特异性CD 4（+）T细胞上显著上调，其参与促进这些细胞的扩增和干扰素-γ的产生，因此一旦T细胞到达肿瘤组织，可能会为T细胞提供共刺激。总的来说，这些结果可能对过继性T细胞治疗具有重要的治疗意义。(c)2005年爱思唯尔公司All rights reserved.
There is an increasing realization that the failure of adoptive therapy with cytotoxic T lymphocytes in the autotogous setting, at least in part, results from the lack of help from antigen-specific CD4(+) T cells. To incorporate these cells into this treatment strategy, it is not known whether currently used ex vivo culture conditions are adequate for expanding and charting these T cells with the desired qualities for optimal in vivo activity. In this study, we show that stimulation with agonistic antibodies to CD3 plus CD28 (anti-CD3/CD28), a commonly used method for CD4(+) T cell expansion, is unable to expand dendritic-cell-activated hepatitis B virus (HBV)-specific CD4(+) T cells to clinical relevant numbers. Whereas, in combination with interieukin(IL)-7 and IL-15, it leads to a 4000-fold expansion of HBV-specific CD4(+) T cells in 2 weeks. This outcome is correlated with the anti-apoptosis effect of IL-7 and IL-15. Importantly, antigen specificity is preserved during expansion. Although a late addition of IL-2 to the anti-CD3 /CD28-expanding cultures also results in robust expansion, this expansion condition renders HBV-specific CD4(+) T cells more sensitive to cytokine withdrawal-, activation-, and transforming growth factor-beta-induced cell death compared to those expanded in IL-7 and IL-15. Moreover, NKG2D rather than 4-1BB, whose ligands are constitutively expressed on tumor cells, is significantly up-regulated on IL-7/IL-15-expanded HBV-specific CD4(+) T cells, and its engagement promotes expansion and interferon-gamma production by these cells and thus may serve to provide co-stimulation to T cells once they reach tumor tissues. Collectively, these results may have important therapeutic implications for adoptive Tcell therapy. (c) 2005 Elsevier Inc. All rights reserved.