T cell repertoire analysis suggests a prominent bystander response in human cardiac allograft vasculopathy.
T cell repertoire analysis suggests a prominent bystander response in human cardiac allograft vasculopathy.
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DOI：
10.1111/ajt.16333
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发表时间：
2021-04
期刊：
影响因子：
--
通讯作者：
Zorn E
中科院分区：
文献类型：
--
作者：
Habal MV;Miller AMI;Rao S;Lin S;Obradovic A;Khosravi-Maharlooei M;See SB;Roy P;Shihab R;Ho SH;Marboe CC;Naka Y;Takeda K;Restaino S;Han A;Mancini D;Givertz M;Madsen JC;Sykes M;Addonizio LJ;Farr MA;Zorn E
T细胞与心脏移植物血管病（CAV）的发病机制有关，但其克隆性、特异性和功能尚不完全清楚。在这里，我们使用T细胞受体β链（TCRB）测序研究了4例CAV患者再次移植时冠状动脉、肌内膜和外周血中的T细胞库，并将其与来自相同样本的免疫球蛋白重链（IGHV）库进行了比较。采用高维流式细胞术结合单细胞PCR确定T细胞表型。在所有病例中，移植物内和血液TCRB之间观察到广泛的重叠，这一发现得到了强大的定量多样性指标的支持。相反，来自相同样品的血液和移植物IGHV库显示最小的重叠。冠状动脉浸润包括表达炎性（IFNγ、TNFα）和促纤维化（TGFβ）细胞因子的CD 4+和CD 8+记忆T细胞。基于记忆、活化和组织驻留标记物（CD 45 RO、CTLA-4和CD 69），这些可与外周血区分开。重要的是，高频率重排可追溯到子宫内膜活检（2-6年前）。与4个HLA不匹配的献血者进行比较，发现了一个共享的TCRB库，包括最近描述的交叉反应序列的子集。这些发现为晚期CAV局部移植物内旁观者T细胞反应的活跃提供了支持性证据。
T cells are implicated in the pathogenesis of cardiac allograft vasculopathy (CAV), yet their clonality, specificity, and function are incompletely defined. Here we used T-cell receptor β chain (TCRB) sequencing to study the T-cell repertoire in the coronary artery, endomyocardium, and peripheral blood at the time of retransplant in 4 cases of CAV and compared it to the immunoglobulin heavy chain (IGHV) repertoire from the same samples. High-dimensional flow cytometry coupled with single-cell PCR was used to define the T-cell phenotype. Extensive overlap was observed between intragraft and blood TCRBs in all cases, a finding supported by robust quantitative diversity metrics. In contrast, blood and graft IGHV repertoires from the same samples showed minimal overlap. Coronary infiltrates included CD4+ and CD8+ memory T cells expressing inflammatory (IFNγ, TNFα) and profibrotic (TGFβ) cytokines. These were distinguishable from the peripheral blood based on memory, activation, and tissue residency markers (CD45RO, CTLA-4 and CD69). Importantly, high frequency rearrangements were traced back to endomyocardial biopsies (2–6 years prior). Comparison with 4 HLA mismatched blood donors revealed a repertoire of shared TCRBs, including a subset of recently described crossreactive sequences. These findings provide supportive evidence for an active local intragraft bystander T-cell response in late-stage CAV.
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