T 细胞功能障碍，包括衰竭、无反应和衰老，是抗原暴露后发生的一种独特的 T 细胞分化状态。尽管 T 细胞功能障碍一直是癌症免疫疗法的基石，但其在移植研究中的潜力虽然尚未得到广泛探索，但正在引起越来越多的兴趣。干扰素调节因子 4 (IRF4) 已被证明在诱导 T 细胞功能障碍中发挥关键作用。采用 Trametinib 和雷帕霉素的新型超低剂量组合，针对 IRF4 抑制，用于研究 T 细胞增殖、凋亡、细胞因子分泌、T 细胞功能障碍相关分子的表达、MAPK 和哺乳动物雷帕霉素靶点 (mTOR) 信号通路的影响，以及体外和 BALB/c 至 C57BL/6 小鼠心脏移植模型中同种异体移植物的存活率。 T细胞中的IRF4有效抑制T细胞增殖，增加细胞凋亡，并显着上调程序性细胞死亡蛋白1（PD-1）、Helios、CD160和细胞毒性T淋巴细胞相关抗原（CTLA-4）（T细胞标志物）的表达。细胞功能障碍。此外，它还抑制促炎细胞因子干扰素 (IFN)-γ 和白细胞介素 (IL)-17 的分泌。结合超低剂量曲美替尼 (0.1 mg·kg-1·day-1) 和雷帕霉素 (0.1 mg·kg-1·day-1) 可明显延长移植物存活期，5 只小鼠中有 4 只在移植后超过 100 天。此外，第 7 天的移植物分析证实了持续的 IFN 调节因子 4 (IRF4) 抑制、增强的 PD-1 表达并抑制 IFN-γ 分泌，增强了这种 IRF4 靶向方法的体内功效。 Trametinib 和 Rapamycin 的组合可协同抑制 MAPK 和 mTOR 信号网络，从而更显着地抑制 IRF4 表达。针对 T 细胞功能障碍的关键调节因子 IRF4，为诱导移植免疫耐受提供了一条有希望的途径。在这项研究中，我们证明了 Trametinib 和雷帕霉素的新型超低剂量组合可协同抑制 MAPK 和 mTOR 信号网络，从而产生深刻的 IRF4 抑制，促进同种异体移植接受，并为改善移植结果提供潜在的新治疗策略。然而，还需要进一步的研究来阐明潜在的药理机制并促进临床实践的转化。版权所有 © 2024 The Chinese Medical Association，由 Wolters Kluwer, Inc. 根据 CC-BY-NC-ND 许可制作。

T cell dysfunction, which includes exhaustion, anergy, and senescence, is a distinct T cell differentiation state that occurs after antigen exposure. Although T cell dysfunction has been a cornerstone of cancer immunotherapy, its potential in transplant research, while not yet as extensively explored, is attracting growing interest. Interferon regulatory factor 4 (IRF4) has been shown to play a pivotal role in inducing T cell dysfunction.A novel ultra-low-dose combination of Trametinib and Rapamycin, targeting IRF4 inhibition, was employed to investigate T cell proliferation, apoptosis, cytokine secretion, expression of T-cell dysfunction-associated molecules, effects of MAPK and mammalian target of Rapamycin (mTOR) signaling pathways, and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models.In vitro, blockade of IRF4 in T cells effectively inhibited T cell proliferation, increased apoptosis, and significantly upregulated the expression of programmed cell death protein 1 (PD-1), Helios, CD160, and cytotoxic T lymphocyte-associated antigen (CTLA-4), markers of T cell dysfunction. Furthermore, it suppressed the secretion of pro-inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17. Combining ultra-low-dose Trametinib (0.1 mg·kg-1·day-1) and Rapamycin (0.1 mg·kg-1·day-1) demonstrably extended graft survival, with 4 out of 5 mice exceeding 100 days post-transplantation. Moreover, analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4 (IRF4) inhibition, enhanced PD-1 expression, and suppressed IFN-γ secretion, reinforcing the in vivo efficacy of this IRF4-targeting approach. The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network, leading to a more pronounced suppression of IRF4 expression.Targeting IRF4, a key regulator of T cell dysfunction, presents a promising avenue for inducing transplant immune tolerance. In this study, we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network, leading to profound IRF4 inhibition, promoting allograft acceptance, and offering a potential new therapeutic strategy for improved transplant outcomes. However, further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.Copyright © 2024 The Chinese Medical Association, produced by Wolters Kluwer, Inc. under the CC-BY-NC-ND license.