Cytotoxic response of human regulatory T cells upon T-cell receptor-mediated activation: a matter of purity
Cytotoxic response of human regulatory T cells upon T-cell receptor-mediated activation: a matter of purity
复制标题
T 细胞受体介导的激活后人类调节性 T 细胞的细胞毒性反应：纯度问题
作者：
S. Koristka;M. Cartellieri;M. Cartellieri;C. Arndt;A. Feldmann;A. Feldmann;Katrin Töpfer;Irene Michalk;Achim Temme;G. Ehninger;M. Bachmann;M. Bachmann
调节性T细胞（Tcells）是免疫稳态的主要参与者，其数量和/或功能的缺陷与广泛的免疫学疾病相关，包括自身免疫、移植物抗宿主病（GvHD）、移植排斥、慢性感染或恶性疾病。2 TGFAP如何主动抑制免疫应答的一种方式可能是直接诱导活化抗原中的细胞凋亡。通过分泌含溶解性颗粒酶和穿孔素的颗粒，在呈递细胞中以及在常规效应T细胞（Tefs）中表达。尽管我们在对Treg生物学的理解方面取得了实质性进展，但TcB的细胞毒性潜力仍在争论中。由于TGFs作为治疗GvHD和移植物排斥的细胞疗法正在进行深入研究，并且还可能干扰新的抗肿瘤策略，3这个问题不是纯粹的学术问题，但也意味着涉及TGFs的临床治疗策略的前瞻性发展的重大后果。为了阐明这一有争议的问题，我们决定使用外周人类T细胞来分析这一问题，因为这些细胞是潜在治疗应用的一个主要来源。1，2由于T细胞是人类外周血中非常罕见的群体，目前在技术上似乎太具有挑战性，以一种可以完成的方式分离足够数量的具有定义的抗原特异性的Treg-例如，病毒或肿瘤特异性Teffs。因此，在这项研究中，重组双特异性抗体（bsAb）应用于抗原特异性重定向的多克隆人T细胞作为替代T细胞受体（TCR）介导的刺激。BsAb包含两种不同靶抗原（例如，CD 3和细胞表面抗原）的结合位点，并且可以直接交联T细胞和抗原表达细胞。这导致主要组织相容性复合体（MHC）和TCR非依赖性激活并触发交联免疫细胞的效应器机制。4 T细胞接合bsAb已被证明在体外高度有效地诱导CD 4+和CD 8 + Teff的裂解能力，在体内甚至在临床试验中，并且非常类似于TCR与其靶肽/MHC复合物结合时诱导的信号级联。
Regulatory T cells (Tregs) are major players in immune homeostasis, and defects in their number and/or function are associated with a broad range of immunological disorders including autoimmunity, graft-versus-host disease (GvHD), transplant rejection, chronic infections or malignant diseases.1, 2 One way of how Tregs actively damp an immune response might be direct induction of apoptosis in activated antigen-presenting cells as well as in conventional effector T cells (Teffs) by secretion of lytic granzyme- and perforin-containing granula. Despite the substantial progress made in our understanding of Treg biology, the cytotoxic potential of Tregs is still under debate. As Tregs are under intense investigation as cellular therapeutics for treatment of GvHD and graft rejection, and might also interfere with novel antitumor strategies,3 this question is not a purely academic one but also implies major consequences for the prospective development of clinical treatment strategies involving Tregs. To shed some light on this controversial issue, we decided to analyze this question using peripheral human Tregs, as these cells are one major source for potential therapeutic applications.1, 2 As Tregs are a very rare population in human peripheral blood, it seems currently technically too challenging to isolate sufficient Treg numbers with defined antigen-specificity in a way as it can be done for—for example, virus- or tumor-specific Teffs. Therefore, in this study recombinant bispecific antibodies (bsAb) were applied for antigen-specific redirection of polyclonal human T cells as surrogate for T-cell receptor (TCR)-mediated stimulation. BsAb comprise binding sites for two different target antigens (for example, CD3 and a cell surface antigen) and can directly cross-link T cells and antigen-expressing cells. This results in a major histocompatibility complex (MHC)- and TCR-independent activation and triggering of effector mechanisms of the cross-linked immune cell.4 T-cell-engaging bsAb have been proven to be highly effective in inducing the lytic capacity of both CD4+ and CD8+ Teffs in vitro, in vivo and even in clinical trials and closely resemble signal cascades induced upon binding of a TCR to its target peptide/MHC complex.4, 5, 6
影响因子：
32.4
作者：
Grossman, WJ;Verbsky, JW;Ley, TJ
通讯作者：
Ley, TJ