Unconventional RORγt+ T Cells Drive Hepatic Ischemia Reperfusion Injury
Unconventional RORγt+ T Cells Drive Hepatic Ischemia Reperfusion Injury
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DOI：
10.4049/jimmunol.1202975
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发表时间：
2013-07-01
影响因子：
4.4
通讯作者：
Kroemer, Alexander
中科院分区：
文献类型：
--
作者：
Eggenhofer, Elke;Rovira, Jordi;Kroemer, Alexander
一个新兴的证据表明，CD 3（+）T细胞在介导早期缺血再灌注损伤（IRI）的关键作用。然而，涉及的T细胞的精确表型和IRI中这种T细胞介导的免疫应答的机制，以及它们的临床相关性，知之甚少。在这项研究中，我们研究了遗传靶向小鼠部分热肝IRI模型中的早期免疫事件，以研究ROR γ t（+）T细胞的确切病理机制作用。我们发现非常规的CD 27（-）γ δ TCR+和CD 4（-）CD 8（-）双阴性T细胞是肝IRI中主要的ROR γ t表达效应细胞，其通过作为IRI介导的IL-17 A的主要来源而发挥机制作用。我们进一步表明，非常规的IRI介导的T细胞是视ROR γ t而定的，正如RORgt的遗传缺陷或其通过地高辛的治疗性去甲化对肝脏IRI具有保护作用这一事实所强调的那样。因此，在肝IRI中通过ROR γ t将CD 27（-）γ δ TCR+和CD 4（-）CD 8（-）双阴性T细胞鉴定为IL-17 A的主要来源为改善肝移植结果开辟了新的治疗选择。
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 ROR gamma t(+) T cells. We found that unconventional CD27(-)gamma delta TCR+ and CD4(-)CD8(-) double-negative T cells are the major ROR gamma t-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 ROR gamma t, as highlighted by the fact that a genetic deficiency for RORgt, or its therapeutic antagonization via digoxin, is protective against hepatic IRI. Therefore, identification of CD27(-)gamma delta TCR+ and CD4(-)CD8(-) double-negative T cells as the major source of IL-17A via ROR gamma t in hepatic IRI opens new therapeutic options to improve liver transplantation outcomes.