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首页> 外文OA文献 >Interleukin-21 (IL-21) synergizes with IL-2 to enhance T-cell receptor-induced human T-cell proliferation and counteracts IL-2/transforming growth factor-beta-induced regulatory T-cell development
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Interleukin-21 (IL-21) synergizes with IL-2 to enhance T-cell receptor-induced human T-cell proliferation and counteracts IL-2/transforming growth factor-beta-induced regulatory T-cell development

机译：白介素21（IL-21）与IL-2协同作用，增强T细胞受体诱导的人T细胞增殖，并抵消IL-2 /转化生长因子-β诱导的调节性T细胞发育

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Interleukin-2 (IL-2) is a mainstay for current immunotherapeutic protocols but its usefulness in patients is reduced by severe toxicities and because IL-2 facilitates regulatory T (Treg) cell development. IL-21 is a type I cytokine acting as a potent T-cell co-mitogen but less efficient than IL-2 in sustaining T-cell proliferation. Using various in vitro models for T-cell receptor (TCR)-dependent human T-cell proliferation, we found that IL-21 synergized with IL-2 to make CD4(+) and CD8(+) T cells attain a level of expansion that was impossible to obtain with IL-2 alone. Synergy was mostly evident in naive CD4(+) cells. IL-2 and tumour-released transforming growth factor-β (TGF-β) are the main environmental cues that cooperate in Treg cell induction in tumour patients. Interleukin-21 hampered Treg cell expansion induced by IL-2/TGF-β combination in naive CD4(+) cells by facilitating non-Treg over Treg cell proliferation from the early phases of cell activation. Conversely, IL-21 did not modulate the conversion of naive activated CD4(+) cells into Treg cells in the absence of cell division. Treg cell reduction was related to persistent activation of Stat3, a negative regulator of Treg cells associated with down-modulation of IL-2/TGF-β-induced phosphorylation of Smad2/3, a positive regulator of Treg cells. In contrast to previous studies, IL-21 was completely ineffective in counteracting the suppressive activity of Treg cells on naive and memory, CD4(+) and CD8(+) T cells. Present data provide proof-of-concept for evaluating a combinatorial approach that would reduce the IL-2 needed to sustain T-cell proliferation efficiently, thereby reducing toxicity and controlling a tolerizing mechanism responsible for the contraction of the T-cell response.
机译：白介素2（IL-2）是当前免疫治疗方案的主要手段，但由于严重的毒性作用以及IL-2促进调节性T（Treg）细胞发育，其在患者中的有用性有所降低。 IL-21是一种I型细胞因子，可作为有效的T细胞共促分裂原，但在维持T细胞增殖方面不如IL-2有效。使用各种体外模型的T细胞受体（TCR）依赖性人类T细胞增殖，我们发现IL-21与IL-2协同作用，使CD4（+）和CD8（+）T细胞达到一定水平的扩增单独使用IL-2是不可能做到的。协同作用在幼稚的CD4（+）细胞中最明显。 IL-2和肿瘤释放的转化生长因子-β（TGF-β）是在肿瘤患者Treg细胞诱导中协同作用的主要环境提示。白细胞介素21通过促进非Treg抑制Treg细胞从细胞活化早期阶段的增殖而抑制了IL-2 /TGF-β组合在幼稚CD4（+）细胞中诱导的Treg细胞扩增。相反，在没有细胞分裂的情况下，IL-21不会调节天然激活的CD4（+）细胞向Treg细胞的转化。 Treg细胞的减少与Stat3的持续激活有关，Stat3是Treg细胞的负调节剂，与IL-2 /TGF-β诱导的Smad2 / 3磷酸化（Treg细胞的正调节剂）的下调有关。与以前的研究相反，IL-21在抵消Treg细胞对幼稚和记忆，CD4（+）和CD8（+）T细胞的抑制活性方面完全无效。当前数据为评估组合方法提供了概念证明，该组合方法将减少有效维持T细胞增殖所需的IL-2，从而降低毒性并控制引起T细胞反应收缩的耐受机制。

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