IL-21 is an antitolerogenic cytokine of the late-phase alloimmune response.
IL-21 is an antitolerogenic cytokine of the late-phase alloimmune response.
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作者：
Petrelli A;Carvello M;Vergani A;Lee KM;Tezza S;Du M;Kleffel S;Chengwen L;Mfarrej BG;Hwu P;Secchi A;Leonard WJ;Young D;Sayegh MH;Markmann JF;Zajac AJ;Fiorina P
白细胞介素-21（IL-21）是一种促炎细胞因子，已显示其影响Treg/Teff平衡。然而，IL-21协调同种免疫应答并与TcB相互作用的机制仍不清楚。IL-21/IL-21 R信号传导、FoxP 3表达和Treg存活和功能之间的相互作用在体外免疫相关测定中以及在胰岛移植的同种异体和自身免疫模型中进行评估。IL-21 R表达在体外T细胞和B细胞上降低，而在体内移植物中增加，而在同种免疫应答的晚期，在抗CD 3/抗CD 28刺激/同种刺激期间，IL-21水平在体外和体内增加。在体外，IL-21/IL-21 R信号传导（通过使用rmIL-21或遗传修饰的CD 4 + T细胞[IL-21 pOrf质粒处理或hIL-21-Tg小鼠]）增强抗CD 3/抗CD 28刺激/同种异体刺激期间的T细胞应答，阻止Treg生成，抑制Treg功能，诱导Treg凋亡，并减少FoxP 3和FoxP 3依赖性基因转录物，而不影响FoxP 3甲基化状态。体内靶向IL-21/IL-21 R可扩增移植物内和外周T细胞，促进Treg新生，并调节抗供体免疫应答，而Doxa诱导的ROSA-rtTA-IL-21-Tg小鼠中的IL-21/IL-21 R信号传导可扩增Tefs和FoxP 3 −细胞。mIL-21 R. Fc和CTLA 4-IG（早期同种免疫反应的抑制剂）联合治疗可在纯同种免疫环境中产生稳健的移植耐受性，并延长NOD小鼠的胰岛移植物存活期。IL-21在同种免疫应答的晚期干扰FoxP 3 Treg链的不同检查点，因此充当抗致耐受性细胞因子。IL-21/IL-21 R通路的阻断可能是移植中致耐受性方案的先决条件。
Interleukin-21 (IL-21) is a proinflammatory cytokine that has been shown to affect Treg/Teff balance. However, the mechanism by which IL-21 orchestrates alloimmune response and interplays with Tregs is still unclear. The interplay between IL-21/IL-21R signaling, FoxP3 expression, and Treg survival and function was evaluated in vitro in immunologically relevant assays and in vivo in allogenic and autoimmune models of islet transplantation. IL-21R expression decreases on T cells and B cells in vitro and increases in the graft in vivo, while IL-21 levels increase in vitro and in vivo during anti-CD3/anti-CD28 stimulation/allostimulation in the late phase of the alloimmune response. In vitro, IL-21/IL-21R signaling (by using rmIL-21 or genetically modified CD4+ T cells [IL-21 pOrf plasmid–treated or hIL-21-Tg mice]) enhances the T-cell response during anti-CD3/anti-CD28 stimulation/allostimulation, prevents Treg generation, inhibits Treg function, induces Treg apoptosis, and reduces FoxP3 and FoxP3-dependent gene transcripts without affecting FoxP3 methylation status. In vivo targeting of IL-21/IL-21R expands intragraft and peripheral Tregs, promotes Treg neogenesis, and regulates the antidonor immune response, whereas IL-21/IL-21R signaling in Doxa-inducible ROSA-rtTA-IL-21-Tg mice expands Teffs and FoxP3− cells. Treatment with a combination of mIL-21R.Fc and CTLA4-Ig (an inhibitor of the early alloimmune response) leads to robust graft tolerance in a purely alloimmune setting and prolonged islet graft survival in NOD mice. IL-21 interferes with different checkpoints of the FoxP3 Treg chain in the late phase of alloimmune response and, thus, acts as an antitolerogenic cytokine. Blockade of the IL-21/IL-21R pathway could be a precondition for tolerogenic protocols in transplantation.
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