Donor Variability and PD-1 Expression Limit BK Polyomavirus-specific T-cell Function and Therapy.

IF 5 2区医学 Q1 IMMUNOLOGY

Transplantation Pub Date : 2025-09-01 Epub Date: 2025-04-09 DOI:10.1097/TP.0000000000005399

Maud Wilhelm, Amandeep Kaur, Anne Geng, Marion Wernli, Hans H Hirsch

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引用次数: 0

Abstract

Background: BK polyomavirus (BKPyV) nephropathy is a major cause of premature kidney transplant failure. Current management relies on reducing immunosuppression to restore BKPyV-specific immune control. Ex vivo expansion and transfer of BKPyV-specific cytotoxic T cells prepared from third-party donors may enhance virus-specific treatment, but the efficacy seems suboptimal.

Methods: To optimize BKPyV-specific T-cell expansion protocols, we compared conventional and G-Rex expansion cultures at 10 and 14 d after stimulation with BKPyV overlapping peptide pools. Cytokine and cytotoxic responses were assessed as well as programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-1L) expression on effector and target cells, respectively.

Results: Despite all donors being BKPyV-IgG seropositive, BKPyV-specific T-cell responses were heterogeneous and varied in magnitude between individuals. Overall, we observed higher cell counts in G-Rex compared to conventional cultures. Upon restimulation with 15mer-pools or immunodominant 9mer-pools, expanded BKPyV-specific T cells expressed polyfunctional markers, for example, interferon-γ, tumor necrosis factor-α and CD107a, and were cytotoxic for 9mP-pulsed autologous phytohemagglutinin blasts or BKPyV-infected allogeneic renal proximal tubule epithelial cells (RPTECs). Compared with conventional cultures, G-Rex-expanded CD4 and CD8 T cells showed higher PD-1 expression. Pembrolizumab reduced PD-1 expression on BKPyV-specific T cells and augmented polyfunctional BKPyV-specific T-cell responses and cytotoxicity. Interferon-𝛾 increased PD-L1 expression on BKPyV-infected RPTECs and increased viability.

Conclusions: Upregulated PD-1 expression of ex vivo expanded T cells contributes to third-party donor variability and potentially impairs the efficacy of adoptive T-cell therapy. Because BKPyV-infected RPTECs increase PD-L1 under inflammatory conditions, adding immune checkpoint inhibitors ex vivo before infusion could be evaluated for enhanced clinical efficacy when attempting treatment of BKPyV-associated pathologies without jeopardizing transplantation outcomes.

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供体变异和PD-1表达限制BK多瘤病毒特异性t细胞功能和治疗

背景：BK 多瘤病毒（BKPyV）肾病是肾移植过早失败的主要原因。目前的治疗方法依赖于减少免疫抑制以恢复 BKPyV 特异性免疫控制。从第三方供体制备的 BKPyV 特异性细胞毒性 T 细胞的体外扩增和转移可增强病毒特异性治疗，但疗效似乎并不理想：为了优化 BKPyV 特异性 T 细胞扩增方案，我们在 BKPyV 重叠肽池刺激后 10 天和 14 天比较了传统扩增培养和 G-Rex 扩增培养。我们评估了细胞因子和细胞毒性反应，以及效应细胞和靶细胞上程序性细胞死亡蛋白 1（PD-1）和程序性细胞死亡配体 1（PD-1L）的表达：尽管所有捐献者的 BKPyV-IgG 血清都呈阳性，但 BKPyV 特异性 T 细胞反应却不尽相同，而且个体之间的反应程度也有差异。总体而言，与传统培养物相比，我们在 G-Rex 中观察到了更高的细胞数量。用 15mer-pools 或免疫显性 9mer-pools 再刺激时，扩增的 BKPyV 特异性 T 细胞表达多种功能标志物，如干扰素-γ、肿瘤坏死因子-α 和 CD107a，并对 9mP 脉冲的自体植物血凝素血块或 BKPyV 感染的异体肾近曲小管上皮细胞（RPTECs）具有细胞毒性。与传统培养相比，G-Rex扩增的CD4和CD8 T细胞显示出更高的PD-1表达。Pembrolizumab能降低BKPyV特异性T细胞上的PD-1表达，增强多功能BKPyV特异性T细胞反应和细胞毒性。干扰素𝛾增加了受BKPyV感染的RPTECs上的PD-L1表达，并提高了存活率：结论：体外扩增 T 细胞的 PD-1 表达上调导致了第三方供体的变异，并有可能损害采纳 T 细胞疗法的疗效。由于受 BKPyV 感染的 RPTECs 会在炎症条件下增加 PD-L1，因此在尝试治疗 BKPyV 相关病症时，可以评估在输注前体内外添加免疫检查点抑制剂以提高临床疗效，同时不影响移植结果。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Transplantation 医学-免疫学

CiteScore

8.50

自引率

11.30%

发文量

1906

审稿时长

1 months

期刊介绍： The official journal of The Transplantation Society, and the International Liver Transplantation Society, Transplantation is published monthly and is the most cited and influential journal in the field, with more than 25,000 citations per year. Transplantation has been the trusted source for extensive and timely coverage of the most important advances in transplantation for over 50 years. The Editors and Editorial Board are an international group of research and clinical leaders that includes many pioneers of the field, representing a diverse range of areas of expertise. This capable editorial team provides thoughtful and thorough peer review, and delivers rapid, careful and insightful editorial evaluation of all manuscripts submitted to the journal. Transplantation is committed to rapid review and publication. The journal remains competitive with a time to first decision of fewer than 21 days. Transplantation was the first in the field to offer CME credit to its peer reviewers for reviews completed. The journal publishes original research articles in original clinical science and original basic science. Short reports bring attention to research at the forefront of the field. Other areas covered include cell therapy and islet transplantation, immunobiology and genomics, and xenotransplantation.