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首页> 外文期刊>Clinical immunology: The official journal of the Clinical Immunology Society >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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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.

机译：具有抗CD3 / CD28，白介素7和白介素15的树突状细胞激活的抗原特异性CD4 + T细胞的离体扩增：过继性T细胞免疫疗法的潜力。

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There is an increasing realization that the failure of adoptive therapy with cytotoxic T lymphocytes in the autologous 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 interleukin(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 T cell therapy.
机译：人们越来越认识到，在自体环境中用细胞毒性T淋巴细胞进行过继治疗的失败至少部分是由于缺乏抗原特异性CD4 + T细胞的帮助。为了将这些细胞整合到该治疗策略中，尚不知道当前使用的离体培养条件是否足以使这些T细胞扩增并绘制出具有最佳体内活性所需质量的T细胞。在这项研究中，我们表明用CD3 + CD28的激动性抗体刺激（抗CD3 / CD28）（一种用于CD4 + T细胞扩增的常用方法）无法扩增树突状细胞激活的乙型肝炎病毒（HBV）特异性CD4 + T细胞达到临床相关数字。而与白介素（IL）-7和IL-15结合使用，可在2周内导致HBV特异性CD4 + T细胞扩展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。尽管在抗CD3 / CD28扩展培养物中后期添加IL-2也会导致强劲的扩增，但这种扩增条件使HBV特异性CD4 + T细胞对细胞因子的撤除，活化和转化生长因子β更加敏感与在IL-7和IL-15中扩增的那些相比，β-β诱导的细胞死亡。此外，配体在肿瘤细胞上组成性表达的NKG2D而不是4-1BB，在IL-7 / IL-15扩增的HBV特异性CD4 + T细胞上显着上调，并且其参与促进扩增和干扰素-γ产生这些细胞可以通过T细胞到达肿瘤组织，从而共同刺激T细胞。总体而言，这些结果可能对过继性T细胞疗法具有重要的治疗意义。

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