Background: The immune checkpoint cytotoxic T lymphocyte antigen-4 (CTLA-4), induced upon T cell activation but degraded quickly, has been targeted in the clinical therapy of advanced cancers and autoimmune diseases. However, whether inhibiting CTLA-4 degradation ameliorates transplant rejection remains unknown./nMethods: The CTLA-4 expression in activated murine T cells treated with the inhibitors mediating protein degradation was detected by flow cytometry (FCM). CD45.1 mice, which received TEa T cells and underwent heart transplantation, were administrated with the inhibitor. Subsequently, CTLA-4 expression of TEa T cells was analyzed. Murine skin and heart transplantation models were built, then the survival and histopathology of the allografts, and T cell subsets in the spleens of each group were compared./nResults: Chloroquine (CQ) was identified as an inhibitor of CTLA-4 degradation, which augmented both surface and total CTLA-4 expression in T cells. It considerably prolonged the skin and heart allograft survival time and reduced the infiltration of inflammatory cells in allografts. Besides decreasing the frequencies of the CD4⁺ and CD8⁺ effector T cells, especially IFN-γ producing T cells, CQ also increased the proportion of regulatory T cells in the spleen. The CTLA-4 blockade abrogated the benefits of CQ on the survival of heart allografts. Moreover, CQ enhanced CTLA-4 expression in activated human T cells and reduced the secretion of IFN-γ in human mixed lymphocyte reaction./nConclusion: Targeting CTLA-4 degradation provides a novel means to prevent transplant rejection and induce transplant tolerance.

中文翻译：

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自噬溶酶体抑制剂氯喹可防止 CTLA-4 降解 T 细胞并减轻小鼠皮肤和心脏移植中的急性排斥反应。

背景：免疫检查点细胞毒性 T 淋巴细胞抗原 4 (CTLA-4) 在 T 细胞活化后诱导但降解迅速，已成为晚期癌症和自身免疫性疾病临床治疗的目标。然而，抑制 CTLA-4 降解是否会改善移植排斥反应仍然未知。/n方法：通过流式细胞术 (FCM) 检测用介导蛋白质降解的抑制剂处理的活化鼠 T 细胞中 CTLA-4 的表达。接受 TEa T 细胞并接受心脏移植的 CD45.1 小鼠被给予抑制剂。随后，分析了TEa T细胞的CTLA-4表达。建立小鼠皮肤和心脏移植模型，然后比较同种异体移植物的存活率和组织病理学，以及各组脾脏中的T细胞亚群。/n结果：氯喹 (CQ) 被鉴定为 CTLA-4 降解的抑制剂，可增强 T 细胞中表面和总 CTLA-4 的表达。它显着延长了皮肤和心脏同种异体移植物的存活时间，并减少了同种异体移植物中炎症细胞的浸润。除了降低 CD4 ⁺和 CD8 ⁺效应 T 细胞，尤其是产生 IFN-γ 的 T 细胞的频率外，CQ 还增加了脾脏中调节性 T 细胞的比例。CTLA-4 阻断消除了 CQ 对心脏同种异体移植物存活的益处。此外，CQ 增强了活化的人 T 细胞中 CTLA-4 的表达，减少了人混合淋巴细胞反应中 IFN-γ 的分泌。/n结论：靶向 CTLA-4 降解提供了一种防止移植排斥和诱导移植耐受的新方法。