Abstract:
Conventional immunosuppressants that suppress allograft rejection cause various side effects. Although regulatory T cells (Tregs) are essential for allograft survival, the limited efficacy of Treg therapy demands improvement. Thus, it is imperative to seek new approaches to enhancing Treg suppression. Low-intensity electrostimulation (ES) has been shown to exert antiinflammatory effects without causing major adverse reactions. However, it remains unknown whether and how ES regulates alloimmunity. Here, we found that regional ES delayed murine skin allograft rejection and promoted long-term allograft survival induced by an mTOR inhibitor, rapamycin. ES also extended islet allograft survival. Mechanistically, ES enhanced the expression of lymphotoxin α (LTα) on Tregs after transplantation. Blockade of lymphotoxin β receptor-mediated nonclassical NFκB signaling suppressed lymphatic Treg migration and largely reversed the effects of ES on allograft survival. Moreover, ES failed to extend allograft survival when recipients lacked LTα/lymph nodes or if transferred Tregs lacked LTα. Therefore, ES promoted the lymphatic migration of CD4+Foxp3+ Tregs by upregulating their surface expression of LTα. Finally, ES augmented expression of LTα on murine or human Tregs, but not conventional T cells, while promoting their calcium influx in vitro. This ES-mediated upregulation of LTα relied on calcium influx. Thus, our findings have unveiled novel mechanisms underlying ES-mediated immunoregulation.
摘要:
抑制同种异体移植物排斥的常规免疫抑制剂引起各种副作用。虽然调节性T细胞(Tregs)是同种异体移植存活所必需的,Treg治疗的有限疗效需要改善。因此,因此,必须寻求新的方法来增强Treg抑制。低强度电刺激(ES)已被证明具有抗炎作用,而不会引起重大不良反应。然而,尚不清楚ES是否以及如何调节同种免疫。我们发现局部ES延迟mTOR抑制剂诱导的小鼠皮肤同种异体移植排斥反应并促进长期同种异体移植存活,雷帕霉素.ES还延长了胰岛同种异体移植物的存活。机械上,ES增强了移植后Tregs上LTα的表达。淋巴毒素β受体(LTβR)介导的非经典NFκB信号传导的阻断抑制了淋巴管Treg的迁移,并在很大程度上逆转了ES对同种异体移植物存活的影响。此外,当接受者缺乏LTα/淋巴结或转移的Tregs缺乏LTα时,ES无法延长同种异体移植物的存活率。因此,ES通过上调CD4+Foxp3+Tregs表面LTα的表达促进其淋巴迁移。最后,ES增强LTα在鼠或人Treg上的表达,但不是传统的T细胞,同时促进它们在体外的钙流入。ES介导的LTα上调依赖于钙内流。因此,我们的发现揭示了ES介导的免疫调节的新机制.