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-β-induced regulatory T-cell development
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-β-induced regulatory T-cell development
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DOI：
10.1111/imm.12061
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发表时间：
2013-05-01
期刊：
影响因子：
6.4
通讯作者：
Fattorossi, Andrea
中科院分区：
文献类型：
--
作者：
Battaglia, Alessandra;Buzzonetti, Alexia;Fattorossi, Andrea
白细胞介素-2（IL-2）是目前免疫方案的支柱，但其在患者中的有用性因严重毒性而降低，并且因为IL-2促进调节性T（Treg）细胞发育。IL-21是一种I型细胞因子，作为有效的T细胞共有丝分裂原，但在维持T细胞增殖方面不如IL-2有效。使用T细胞受体（TCR）依赖性人T细胞增殖的各种体外模型，我们发现IL-21与IL-2协同作用使CD 4+和CD 8 + T细胞达到单独使用IL-2不可能获得的扩增水平。协同作用在初始CD 4+细胞中最明显。IL-2和肿瘤释放的转化生长因子（TGF-β）是在肿瘤患者中协同诱导Treg细胞的主要环境因子。白细胞介素-21通过从细胞活化的早期阶段促进非Treg细胞相对于Treg细胞的增殖，阻碍了由IL-2/TGF-β组合在初始CD 4+细胞中诱导的Treg细胞扩增。相反，IL-21在细胞分裂不存在的情况下不调节初始活化的CD 4+细胞向Treg细胞的转化。Treg细胞减少与Stat 3的持续激活有关，Stat 3是Treg细胞的负调节因子，与IL-2/TGF-β诱导的Smad 2/3磷酸化的下调有关，Smad 2/3是Treg细胞的正调节因子。与先前的研究相反，IL-21在抵消Treg细胞对幼稚和记忆、CD 4+和CD 8 + T细胞的抑制活性方面完全无效。目前的数据提供了用于评估组合方法的概念验证，所述组合方法将有效地减少维持T细胞增殖所需的IL-2，从而降低毒性并控制负责T细胞应答收缩的耐受化机制。
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- (TGF-) 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- 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--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.