Department of Surgery, University Hospital Regensburg, University of Regensburg, 93053 Regensburg, Germany.
J Immunol. 2013 Jul 1;191(1):480-7. doi: 10.4049/jimmunol.1202975. Epub 2013 Jun 5.
An emerging body of evidence suggests a pivotal role of CD3(+) T cells in mediating early ischemia reperfusion injury (IRI). However, the precise phenotype of T cells involved and the mechanisms underlying such T cell-mediated immune responses in IRI, as well as their clinical relevance, are poorly understood. In this study, we investigated early immunological events in a model of partial warm hepatic IRI in genetically targeted mice to study the precise pathomechanistic role of RORγt(+) T cells. We found that unconventional CD27(-)γδTCR(+) and CD4(-)CD8(-) double-negative T cells are the major RORγt-expressing effector cells in hepatic IRI that play a mechanistic role by being the main source of IRI-mediating IL-17A. We further show that unconventional IRI-mediating T cells are contingent on RORγt, as highlighted by the fact that a genetic deficiency for RORγt, or its therapeutic antagonization via digoxin, is protective against hepatic IRI. Therefore, identification of CD27(-)γδTCR(+) and CD4(-)CD8(-) double-negative T cells as the major source of IL-17A via RORγt in hepatic IRI opens new therapeutic options to improve liver transplantation outcomes.
越来越多的证据表明，CD3(+) T 细胞在介导早期缺血再灌注损伤 (IRI) 中起着关键作用。然而，人们对涉及的 T 细胞的确切表型以及 IRI 中这种 T 细胞介导的免疫反应的机制及其临床相关性知之甚少。在这项研究中，我们研究了基因靶向小鼠部分温热性肝 IRI 模型中的早期免疫学事件，以研究 RORγt(+) T 细胞在确切的病理机制中的作用。我们发现，非传统的 CD27(-)γδTCR(+)和 CD4(-)CD8(-)双阴性 T 细胞是肝 IRI 中主要表达 RORγt 的效应细胞，通过作为介导 IRI 的 IL-17A 的主要来源发挥作用。我们进一步表明，非传统的 IRI 介导的 T 细胞依赖于 RORγt，因为 RORγt 的基因缺失或通过洋地黄毒苷进行其治疗性拮抗作用可防止肝 IRI，这一事实突出了这一点。因此，通过 RORγt 将 CD27(-)γδTCR(+)和 CD4(-)CD8(-)双阴性 T 细胞鉴定为肝 IRI 中 IL-17A 的主要来源，为改善肝移植结果提供了新的治疗选择。
