Liver inflammation abrogates immunological tolerance induced by Kupffer cells
Liver inflammation abrogates immunological tolerance induced by Kupffer cells
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DOI：
10.1002/hep.27793
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发表时间：
2015-07-01
期刊：
影响因子：
13.5
通讯作者：
Tacke, Frank
中科院分区：
文献类型：
--
作者：
Heymann, Felix;Peusquens, Julia;Tacke, Frank
肝脏对于诱导对无害抗原的免疫耐受以维持免疫系统稳态是必不可少的。然而，对颗粒结合抗原的耐受性诱导的精确细胞机制，局部肝脏微环境的作用，以及对免疫介导疾病的治疗靶点的影响目前尚不清楚。为了阐明在健康和受伤的肝脏中诱导耐受的细胞机制，我们开发了一种新的体内系统，该系统结合了与惰性颗粒偶联的低剂量肽抗原的全身递送、免疫学读数和复杂的基于活体多光子显微镜的小鼠肝脏成像。我们发现，肝脏居民巨噬细胞，枯否细胞（KCs），但不是肝单核细胞衍生的巨噬细胞或树突状细胞（DC），是中央细胞清除循环颗粒相关抗原的稳态。KC相关抗原呈递诱导CD4 T细胞停滞、天然存在的Foxp3（+）CD25（+）白介素-10产生抗原特异性调节性T细胞（TCLs）的扩增和致耐受性免疫。肝脏中颗粒相关的耐受诱导可以保护小鼠免受T细胞介导的肾小球肾炎中的肾脏炎症，这表明靶向KC对免疫介导的肝外疾病的治疗潜力。在慢性肝损伤和纤维化的两个独立实验模型中，肝脏炎症消除了耐受诱导，并导致抗原特异性CD4 T细胞的免疫原性重编程。在损伤的肝脏中，浸润的单核细胞衍生的巨噬细胞在很大程度上增加了肝脏吞噬细胞区室，导致骨髓细胞群体之间的抗原重新分布，同时，KC失去了其致耐受性表型的标志物。结论：肝脏诱导对颗粒抗原的组织保护性免疫耐受依赖于KCs以及非炎症的肝脏微环境，从而为晚期肝病患者的免疫功能障碍和耐受性破坏的临床观察提供了机制解释。（肝病学2015; 62：279 - 291）
The liver is essential for inducing immunological tolerance toward harmless antigens to maintain immune system homeostasis. However, the precise cellular mechanisms of tolerance induction against particle-bound antigens, the role of the local hepatic microenvironment, and implications for therapeutic targets in immune-mediated diseases are currently unclear. In order to elucidate cellular mechanisms of tolerance induction in healthy and injured liver, we developed a novel in vivo system combining the systemic delivery of low-dose peptide antigens coupled to inert particles, immunological readouts, and sophisticated intravital multiphoton microscopy-based imaging of liver in mice. We show that liver resident macrophages, Kupffer cells (KCs), but not hepatic monocyte-derived macrophages or dendritic cells (DCs), are the central cellular scavenger for circulating particle-associated antigens in homeostasis. KC-associated antigen presentation induces CD4 T-cell arrest, expansion of naturally occurring Foxp3(+)CD25(+) interleukin-10-producing antigen-specific regulatory T cells (Tregs) and tolerogenic immunity. Particle-associated tolerance induction in the liver protected mice from kidney inflammation in T-cell-mediated glomerulonephritis, indicating therapeutic potential of targeting KC for immune-mediated extrahepatic disorders. Liver inflammation in two independent experimental models of chronic liver injury and fibrosis abrogated tolerance induction and led to an immunogenic reprogramming of antigen-specific CD4 T cells. In injured liver, infiltrating monocyte-derived macrophages largely augment the hepatic phagocyte compartment, resulting in antigen redistribution between myeloid cell populations and, simultaneously, KCs lose signature markers of their tolerogenic phenotype. Conclusions: Hepatic induction of tissue-protective immunological tolerance against particulate antigens is dependent on KCs as well as on a noninflamed liver microenvironment, thereby providing mechanistic explanations for the clinical observation of immune dysfunction and tolerance break in patients with advanced liver diseases. (Hepatology 2015;62:279-291)