Centre Hospitalier Universitaire de Poitiers, Institut National de la Santé Et de la Recherche Médicale, Ischemie Reperfusion Métabolisme et Inflammation Stérile en Transplantation, Université de Poitiers, Poitiers, France.
Institut National de la Santé Et de la Recherche Médicale (INSERM), Ischemie Reperfusion Métabolisme et Inflammation Stérile en Transplantation (IRMETIST), Université de Poitiers, Poitiers, France.
Front Immunol. 2023 May 9;14:1099529. doi: 10.3389/fimmu.2023.1099529. eCollection 2023.
Over the past thirty years, the complexity of the αβ-T cell compartment has been enriched by the identification of innate-like T cells (ITCs), which are composed mainly of invariant natural killer T (iNKT) cells and mucosal-associated invariant T (MAIT) cells. Based on animal studies using ischemia-reperfusion (IR) models, a key role has been attributed to iNKT cells in close connection with the alarmin/cytokine interleukin (IL)-33, as early sensors of cell-stress in the initiation of acute sterile inflammation. Here we have investigated whether the new concept of a biological axis of circulating iNKT cells and IL-33 applies to humans, and may be extended to other ITC subsets, namely MAIT and γδ-T cells, in the acute sterile inflammation sequence occurring during liver transplant (LT). From a prospective biological collection of recipients, we reported that LT was accompanied by an early and preferential activation of iNKT cells, as attested by almost 40% of cells having acquired the expression of CD69 at the end of LT (i.e. 1-3 hours after portal reperfusion), as opposed to only 3-4% of conventional T cells. Early activation of iNKT cells was positively correlated with the systemic release of the alarmin IL-33 at graft reperfusion. Moreover, in a mouse model of hepatic IR, iNKT cells were activated in the periphery (spleen), and recruited in the liver in WT mice, as early as the first hour after reperfusion, whereas this phenomenon was virtually missing in IL-33-deficient mice. Although to a lesser degree than iNKT cells, MAIT and γδ-T cells also seemed targeted during LT, as attested by 30% and 10% of them acquiring CD69 expression, respectively. Like iNKT cells, and in clear contrast to γδ-T cells, activation of MAIT cells during LT was closely associated with both release of IL-33 immediately after graft reperfusion and severity of liver dysfunction occurring during the first three post-operative days. All in all, this study identifies iNKT and MAIT cells in connection with IL-33 as new key cellular factors and mechanisms of acute sterile inflammation in humans. Further investigations are required to confirm the implication of MAIT and iNKT cell subsets, and to precisely assess their functions, in the clinical course of sterile inflammation accompanying LT.
在过去的三十年中，通过鉴定先天样 T 细胞（ITC），αβ-T 细胞区室的复杂性得到了丰富，这些细胞主要由不变自然杀伤 T（iNKT）细胞和黏膜相关不变 T（MAIT）细胞组成。基于使用缺血再灌注（IR）模型的动物研究，iNKT 细胞在与警报素/细胞因子白细胞介素（IL）-33 的紧密联系中被赋予了关键作用，作为急性无菌性炎症起始时细胞应激的早期传感器。在这里，我们研究了循环 iNKT 细胞和 IL-33 的新生物学轴的概念是否适用于人类，并可能扩展到其他 ITC 亚群，即 MAIT 和 γδ-T 细胞，在发生肝移植（LT）期间的急性无菌性炎症序列中。从受者的前瞻性生物学采集中，我们报告说 LT 伴随着 iNKT 细胞的早期和优先激活，这证明了几乎 40%的细胞在 LT 结束时（即门静脉再灌注后 1-3 小时）获得了 CD69 的表达，而只有 3-4%的常规 T 细胞。iNKT 细胞的早期激活与移植物再灌注时警报素 IL-33 的全身释放呈正相关。此外，在肝 IR 的小鼠模型中，iNKT 细胞在脾脏等外周组织中被激活，并在 WT 小鼠中在再灌注后第一小时就招募到肝脏中，而在 IL-33 缺陷型小鼠中几乎没有这种现象。尽管程度低于 iNKT 细胞，但 MAIT 和 γδ-T 细胞在 LT 期间也似乎受到靶向，这证明它们分别有 30%和 10%获得了 CD69 的表达。与 iNKT 细胞一样，并且与 γδ-T 细胞形成鲜明对比，MAIT 细胞在 LT 期间的激活与移植物再灌注后立即释放 IL-33 以及术后前三天发生的肝功能障碍严重程度密切相关。总而言之，这项研究确定了与 IL-33 相关的 iNKT 和 MAIT 细胞作为人类急性无菌性炎症的新关键细胞因子和机制。需要进一步的研究来确认 MAIT 和 iNKT 细胞亚群的作用，并准确评估它们在伴随 LT 的无菌性炎症的临床过程中的作用。
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