Transplantation Research Center, Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Diabetes. 2011 Dec;60(12):3223-34. doi: 10.2337/db11-0880. Epub 2011 Oct 19.
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.
白细胞介素 21（IL-21）是一种促炎细胞因子，已被证明会影响 Treg/Teff 平衡。然而，IL-21 协调同种免疫反应并与 Tregs 相互作用的机制尚不清楚。
在免疫相关的体外测定和同种异体和自身免疫性胰岛移植模型中体内评估了 IL-21/IL-21R 信号、FoxP3 表达以及 Treg 存活和功能之间的相互作用。
体外 T 细胞和 B 细胞上的 IL-21R 表达减少，体内移植物中增加，而体外和体内抗 CD3/抗 CD28 刺激/同种刺激的晚期 IL-21 水平增加。在体外，IL-21/IL-21R 信号（使用 rmIL-21 或基因修饰的 CD4(+)T 细胞[IL-21 pOrf 质粒处理或 hIL-21-Tg 小鼠]）增强抗 CD3/抗 CD28 刺激/同种刺激期间的 T 细胞反应，阻止 Treg 的产生，抑制 Treg 功能，诱导 Treg 凋亡，并减少 FoxP3 和 FoxP3 依赖性基因转录，而不影响 FoxP3 甲基化状态。体内靶向 IL-21/IL-21R 可扩大移植物内和外周 Treg，促进 Treg 新生，并调节抗供体免疫反应，而 Doxa 诱导的 ROSA-rtTA-IL-21-Tg 小鼠中的 IL-21/IL-21R 信号则扩增 Teffs 和 FoxP3(-)细胞。mIL-21R.Fc 和 CTLA4-Ig（早期同种免疫反应抑制剂）的联合治疗可在纯同种免疫环境中导致强烈的移植物耐受，并延长 NOD 小鼠的胰岛移植物存活时间。
IL-21 在同种免疫反应的晚期干扰 FoxP3 Treg 链的不同检查点，因此作为一种抗耐受细胞因子。阻断 IL-21/IL-21R 途径可能是移植中耐受原性方案的前提条件。
