Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China; Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China.
Department of Immunology, Fourth Military Medical University, Xi'an, Shaanxi, China.
Am J Transplant. 2023 Jul;23(7):920-934. doi: 10.1016/j.ajt.2023.04.007. Epub 2023 Apr 11.
End-stage organ failure often requires solid organ transplantation. Nevertheless, transplant rejection remains an unresolved issue. The induction of donor-specific tolerance is the ultimate goal in transplantation research. In this study, an allograft vascularized skin rejection model using BALB/c-C57/BL6 mice was established to evaluate the regulation of the poliovirus receptor signaling pathway using CD226 knockout or T cell immunoglobulin and ITIM domain (TIGIT)-crystallizable fragment (Fc) recombinant protein treatment. In the TIGIT-Fc-treated and CD226 knockout groups, graft survival time prolonged significantly, with a regulatory T cell proportion increase and M2-type macrophage polarization. Donor-reactive recipient T cells became hyporesponsive while responding normally after a third-party antigen challenge. In both groups, serum interleukin (IL)-1β, IL-6, IL-12p70, IL-17A, tumor necrosis factor-α, interferon gamma, and monocyte chemoattractant protein-1 levels decreased, and the IL-10 level increased. In vitro, M2 markers, such as Arg1 and IL-10, were markedly increased by TIGIT-Fc, whereas iNOS, IL-1β, IL-6, IL-12p70, tumor necrosis factor-α, and interferon gamma levels decreased. CD226-Fc exerted the opposite effect. TIGIT suppressed T1 and T17 differentiation by inhibiting macrophage SHP-1 phosphorylation and enhanced ERK1/2-MSK1 phosphorylation and nuclear translocation of CREB. In conclusion, CD226 and TIGIT competitively bind to poliovirus receptor with activating and inhibitory functions, respectively. Mechanistically, TIGIT promotes IL-10 transcription from macrophages by activating the ERK1/2-MSK1-CREB pathway and enhancing M2-type polarization. CD226/TIGIT-poliovirus receptor are crucial regulatory molecules of allograft rejection.
终末期器官衰竭通常需要进行实体器官移植。然而，移植排斥仍是一个尚未解决的问题。诱导供体特异性耐受是移植研究的最终目标。在这项研究中，我们建立了一种使用 BALB/c-C57/BL6 小鼠的同种异体血管化皮肤排斥模型，以评估使用 CD226 敲除或 T 细胞免疫球蛋白和 ITIM 结构域（TIGIT）-可结晶片段（Fc）重组蛋白治疗调节脊髓灰质炎病毒受体信号通路。在 TIGIT-Fc 处理和 CD226 敲除组中，移植物存活时间显著延长，调节性 T 细胞比例增加，M2 型巨噬细胞极化。供体反应性受者 T 细胞在受到第三方抗原刺激后反应正常，但反应性降低。在这两组中，血清白细胞介素（IL）-1β、IL-6、IL-12p70、IL-17A、肿瘤坏死因子-α、干扰素γ和单核细胞趋化蛋白-1 水平降低，IL-10 水平升高。体外实验结果表明，TIGIT-Fc 可显著增加 M2 标志物 Arg1 和 IL-10 的表达，而 iNOS、IL-1β、IL-6、IL-12p70、肿瘤坏死因子-α和干扰素γ的水平降低。CD226-Fc 则发挥相反的作用。TIGIT 通过抑制巨噬细胞 SHP-1 磷酸化，增强 ERK1/2-MSK1 磷酸化和 CREB 的核转位，抑制 T1 和 T17 分化。总之，CD226 和 TIGIT 分别通过激活和抑制作用竞争结合脊髓灰质炎病毒受体。从机制上讲，TIGIT 通过激活 ERK1/2-MSK1-CREB 通路和增强 M2 型极化来促进巨噬细胞中 IL-10 的转录。CD226/TIGIT-脊髓灰质炎病毒受体是同种异体排斥反应的关键调节分子。
