Selective Effects of mTOR Inhibitor Sirolimus on Naive and CMV-Specific T Cells Extending Its Applicable Range Beyond Immunosuppression
Selective Effects of mTOR Inhibitor Sirolimus on Naive and CMV-Specific T Cells Extending Its Applicable Range Beyond Immunosuppression
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DOI：
10.3389/fimmu.2018.02953
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发表时间：
2018-12-17
影响因子：
7.3
通讯作者：
Eiz-Vesper, Britta
中科院分区：
文献类型：
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作者：
Bak, Szilvia;Tischer, Sabine;Eiz-Vesper, Britta
巨细胞病毒（CMV）感染/再激活仍然是移植后免疫抑制最重要的并发症之一。然而，最近的临床观察表明，用西罗莫司抑制哺乳动物雷帕霉素靶点 (mTOR) 可能会改善 CMV 并发症的结果。这一观察结果的潜在机制，特别是西罗莫司对幼稚和 CMV 特异性细胞毒性 CD8(+) T 细胞 (CMV-CTL) 功能的影响尚未被发现。在此，通过 CD3/CD28 交联和同种异体反应性测定确定西罗莫司对初始和记忆 CMV-CTL 的影响。用 HLA-A*02:01 限制性 CMVpp65 肽负载的人工抗原呈递细胞 (aAPC) 刺激 CMV-CTL 后，我们测量了西罗莫司对 T 细胞增殖、表型和功能的影响。西罗莫司显着改善 CMV 特异性效应记忆 T 细胞功能，并对初始 T 细胞产生负面影响。这种独特的作用机制的进一步特点是增加干扰素-γ (IFN-γ)、颗粒酶 B (GzB) 的分泌，并增强激活的 CMV-CTL 的靶细胞依赖性细胞毒能力。应用下一代测序 (NGS) 监测 T 细胞受体 (TCR) 库动态，并验证功能性的增加与西罗莫司耐药的 CTL 克隆无关。相反，在 mTOR 抑制下，通过 IL-2 受体 (IL-2R) 驱动的信号转导器和转录 5 (STAT-5) 信号激活剂在 CMV-CTL 发育过程中调节环境线索，可以微调 T 细胞编程，从而增强抗病毒反应并具有稳定的 TCR 动态。我们首次证明西罗莫司选择性地作用于人类幼稚和记忆 T 细胞，并通过调节环境环境来改善 CMV 特异性 T 细胞功能。这些数据强调了扩大免疫监测（包括细胞因子水平和 T 细胞功能）的重要性，这将有助于识别可能受益于个体化免疫抑制的患者。
Cytomegalovirus (CMV) infection/reactivation remains among the most important complications of immunosuppression after transplantation. However, recent clinical observations indicate that mammalian target of rapamycin (mTOR) inhibition with sirolimus may improve the outcome of CMV complications. Underlying mechanisms of this observation, particularly the effect of sirolimus on naive-and CMV-specific cytotoxic CD8(+) T-cell (CMV-CTL) functionality is still undiscovered. Here, the influence of sirolimus on naive and memory CMV-CTLs was determined by CD3/CD28 crosslinking and alloreactivity assays. After stimulating CMV-CTL with HLA-A*02: 01-restricted CMVpp65-peptide loaded artificial antigen-presenting cells (aAPCs), we measured the effect of sirolimus on T-cell proliferation, phenotype, and functionality. Sirolimus significantly improved CMV-specific effector memory T-cell function and negatively influenced naive T cells. This unique mechanism of action was further characterized by increased secretion of interferon-gamma (IFN-gamma), granzyme B (GzB) and enhanced target-cell-dependent cytotoxic capacity of activated CMV-CTLs. Next-generation-sequencing (NGS) was applied to monitor T-cell receptor (TCR)-repertoire dynamics and to verify, that the increased functionality was not related to sirolimus-resistant CTL-clones. Instead, modulation of environmental cues during CMV-CTL development via IL-2 receptor (IL-2R)-driven signal transducer and activator of transcription-5 (STAT-5) signaling under mTOR inhibition allowed fine-tuning of T-cell programming for enhanced antiviral response with stable TCR-repertoire dynamics. We show for the first time that sirolimus acts selectively on human naive and memory T cells and improves CMV-specific T-cell function via modulation of the environmental milieu. The data emphasize the importance to extend immune monitoring including cytokine levels and T-cell functionality which will help to identify patients who may benefit from individually tailored immunosuppression.