Human CD45RA- FoxP3hi Memory-Type Regulatory T Cells Show Distinct TCR Repertoires With Conventional T Cells and Play an Important Role in Controlling Early Immune Activation
Human CD45RA- FoxP3hi Memory-Type Regulatory T Cells Show Distinct TCR Repertoires With Conventional T Cells and Play an Important Role in Controlling Early Immune Activation
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DOI：
10.1111/ajt.13315
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发表时间：
2015-10-01
影响因子：
8.8
通讯作者：
Volk, H. -D.
中科院分区：
文献类型：
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作者：
Lei, H.;Kuchenbecker, L.;Volk, H. -D.
调节性T细胞（Treg）过继免疫治疗是促进实体器官移植（SOT）后免疫耐受的新选择。然而，等待移植的老年患者的Treg以CD45RA(-)CD62L（+）中枢记忆型Treg亚群（TregCM）为主，且表征良好且稳定的初始Treg （TregN）的产量较低。因此，确定这些TregCM是否来源于胸腺，是否像TregN一样表达高稳定性、抑制能力和广泛的抗原库是很重要的。在这项研究中，我们发现TregCM使用不同于传统T细胞（Tconv）的T细胞受体（TCR）库，使用所有24个V β家族的新一代测序，平均深度为534 677个序列。这表明诱导的Treg几乎没有污染。此外，TregCM在控制激活标志物表达和细胞因子分泌的免疫激活早期检查点对Tconv的抑制活性增强，但对增殖的抑制作用相当。在mTOR抑制下体外扩增后，TregCM和TregN同样扩增而不丧失其功能。尽管TCR曲目相对有限，TregCM也表现出特异性的同种异体反应，尽管与TregN相比略有减少。这些结果支持从富含CD45RA(-)CD62L(+) Treg的起始材料制造Treg产品用于过继性Treg治疗的治疗有效性。
Adoptive immunotherapy with regulatory T cells (Treg) is a new option to promote immune tolerance following solid organ transplantation (SOT). However, Treg from elderly patients awaiting transplantation are dominated by the CD45RA(-)CD62L(+) central memory type Treg subset (TregCM), and the yield of well-characterized and stable naive Treg (TregN) is low. It is, therefore, important to determine whether these TregCM are derived from the thymus and express high stability, suppressive capacity and a broad antigen repertoire like TregN. In this study, we showed that TregCM use a different T cell receptor (TCR) repertoire from conventional T cells (Tconv), using next-generation sequencing of all 24 V beta families, with an average depth of 534 677 sequences. This showed almost no contamination with induced Treg. Furthermore, TregCM showed enhanced suppressive activity on Tconv at early checkpoints of immune activation controlling activation markers expression and cytokine secretion, but comparable inhibition of proliferation. Following in vitro expansion under mTOR inhibition, TregCM expanded equally as well as TregN without losing their function. Despite relatively limited TCR repertoire, TregCM also showed specific alloresponse, although slightly reduced compared to TregN. These results support the therapeutic usefulness of manufacturing Treg products from CD45RA(-)CD62L(+) Treg-enriched starting material to be applied for adoptive Treg therapy.