由于死亡受体FAS介导的途径失活，急性肝移植排斥反应（ARJ）的主要介导者——异体免疫刺激的CD8+ T细胞（aCD8+ T细胞），对凋亡具有低敏感性，并且无法诱导耐受，最终导致急性移植物排斥。临床上最常用的免疫抑制剂（IS）他克莫司（FK506）虽然能够诱导容纳，但其靶免疫细胞未知，并且与增加的恶性肿瘤、感染和肾毒性的发生率升高相关，这对长期肝移植（LTx）结果产生重大影响。暗褐色大鼠（DA）- 到 联系鼠 (Lewis rat) 的肝移植模型是一个众所周知的ARJ模型，因此被选用于本研究。我们发现，肝细胞生长因子（hepatocyte growth factor，HGF）（cHGF，含有主要促进HGF产生的形式）和重组HGF（h-rHGF）通过抑制cMet对FAS拮抗作用和Fas三聚化，从而通过FAS介导的凋亡途径对同种异体aCD8+ T细胞抑制发挥免疫调节作用，从而诱导急性耐受。我们还发现，这种抑制作用可以通过对cMet（只有HGF受体）用中和抗体进行处理来取消。相反，我们并未观察到FK506对大鼠具有这些效应。然而，我们观察到FK506的抗排斥作用主要是通过抑制异体免疫刺激的CD4+ T细胞（aCD4+ T细胞）和促进调节性T细胞（Treg）来实现的，与HGF的作用机制不同。此外，我们还阐述了HGF在FK506介导的肾毒性中的保护机制。因此，无论是与FK506联合使用还是作为单独治疗，HGF作为耐受诱导剂可能具有良好的临床价值。对这些T细胞亚群在其他生物系统中的额外作用以及在这些领域的研究也将具有意义。 版权所有 © 2023 Chen, Yang, Lin, Lai, Hu, Yan, Wu, Liu, Li, He, Sun, Shuai, Peng, Wang, Li, Cui, Zhang, Zhang and Bai.

Allostimulated CD8+ T cells (aCD8+ T cells), as the main mediators of acute liver rejection (ARJ), are hyposensitive to apoptosis due to the inactivation of death receptor FAS-mediated pathways and fail to allow tolerance induction, eventually leading to acute graft rejection. Although tacrolimus (FK506), the most commonly used immunosuppressant (IS) in the clinic, allows tolerance induction, its use is limited because its target immune cells are unknown and it is associated with increased incidences of malignancy, infection, and nephrotoxicity, which substantially impact long-term liver transplantation (LTx) outcomes. The dark agouti (DA)-to-Lewis rat LTx model is a well-known ARJ model and was hence chosen for the present study. We show that both hepatocyte growth factor (HGF) (cHGF, containing the main form of promoting HGF production) and recombinant HGF (h-rHGF) exert immunoregulatory effects mainly on allogeneic aCD8+ T cell suppression through FAS-mediated apoptotic pathways by inhibiting cMet to FAS antagonism and Fas trimerization, leading to acute tolerance induction. We also showed that such inhibition can be abrogated by treatment with neutralizing antibodies against cMet (HGF-only receptor). In contrast, we did not observe these effects in rats treated with FK506. However, we observed that the effect of anti-rejection by FK506 was mainly on allostimulated CD4+ T cell (aCD4+ T cell) suppression and regulatory T cell (Treg) promotion, in contrast to the mechanism of HGF. In addition, the protective mechanism of HGF in FK506-mediated nephrotoxicity was addressed. Therefore, HGF as a tolerance inducer, whether used in combination with FK506 or as monotherapy, may have good clinical value. Additional roles of these T-cell subpopulations in other biological systems and studies in these fields will also be meaningful.Copyright © 2023 Chen, Yang, Lin, Lai, Hu, Yan, Wu, Liu, Li, He, Sun, Shuai, Peng, Wang, Li, Cui, Zhang, Zhang and Bai.