Miller-Handley Hilary, Harper Gavin, Pham Giang, Turner Lucien H, Shao Tzu-Yu, Russi Abigail E, Erickson John J, Ford Mandy L, Araki Koichi, Way Sing Sing
Division of Infectious Diseases, Center for Inflammation and Tolerance, Department of Pediatrics, Cincinnati Children's Hospital, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States.
J Immunol. 2025 Jan 1;214(1):192-198. doi: 10.1093/jimmun/vkae007.
Organ transplant recipients require continual immune-suppressive therapies to sustain allograft acceptance. Although medication nonadherence is a major cause of rejection, the mechanisms responsible for graft loss in this clinically relevant context among individuals with preceding graft acceptance remain uncertain. Here, we demonstrate that skin allograft acceptance in mice maintained with clinically relevant immune-suppressive therapies, tacrolimus and mycophenolate, sensitizes hypofunctional PD1hi graft-specific CD8+ T cells. Uninterrupted immune-suppressive therapy is required because drug discontinuation triggers allograft rejection, replicating the requirement for immune-suppressive therapy adherence in transplant recipients. Graft-specific CD8+ T cells in allograft-accepted mice show diminished effector differentiation and cytokine production, with reciprocally increased PD1 expression. Allograft acceptance-induced PD1 expression is essential, as PDL1 blockade reinvigorates graft-specific CD8+ T cell activation with ensuing allograft rejection despite continual immune-suppressive therapy. Thus, PD1 sustained CD8+ T cell inhibition is essential for allograft acceptance maintained by tacrolimus plus mycophenolate. This necessity for PD1 in sustaining allograft acceptance explains the high rates of rejection in transplant recipients with cancer administered immune checkpoint inhibitors targeting PD1/PDL1, highlighting shared immune suppression pathways exploited by tumor cells and current therapies for averting allograft rejection.
器官移植受者需要持续的免疫抑制疗法来维持同种异体移植物的存活。尽管药物不依从是排斥反应的主要原因，但在先前已接受移植物的个体中，导致移植物丢失的机制在这种临床相关情况下仍不明确。在此，我们证明，在使用临床相关免疫抑制疗法他克莫司和霉酚酸维持的小鼠中，皮肤同种异体移植物的接受会使功能低下的PD1高表达的移植物特异性CD8+T细胞致敏。需要不间断的免疫抑制治疗，因为停药会引发同种异体移植物排斥反应，这与移植受者对免疫抑制治疗依从性的要求相符。接受同种异体移植物的小鼠中的移植物特异性CD8+T细胞显示效应细胞分化和细胞因子产生减少，而PD1表达则相应增加。同种异体移植物接受诱导的PD1表达至关重要，因为尽管持续进行免疫抑制治疗，但PDL1阻断会恢复移植物特异性CD8+T细胞的活化，并随之引发同种异体移植物排斥反应。因此，PD1持续抑制CD8+T细胞对于他克莫司加霉酚酸维持的同种异体移植物接受至关重要。PD1在维持同种异体移植物接受中的这种必要性解释了接受针对PD1/PDL1的免疫检查点抑制剂治疗的癌症移植受者中排斥反应的高发生率，突出了肿瘤细胞利用的共同免疫抑制途径以及目前用于避免同种异体移植物排斥反应的疗法。
