von Oppen Nanette, Schurich Anna, Hegenbarth Silke, Stabenow Dirk, Tolba Rene, Weiskirchen Ralf, Geerts Albert, Kolanus Waldemar, Knolle Percy, Diehl Linda
Institute of Molecular Medicine and Experimental Immunology, University Hospital Aachen, Aachen, Germany.
Hepatology. 2009 May;49(5):1664-72. doi: 10.1002/hep.22795.
Peripheral CD8 T-cell tolerance can be generated outside lymphatic tissue in the liver, but the course of events leading to tolerogenic interaction of hepatic cell populations with circulating T-cells remain largely undefined. Here we demonstrate that preferential uptake of systemically circulating antigen by murine liver sinusoidal endothelial cells (LSECs), and not by other antigen-presenting cells in the liver or spleen, leads to cross-presentation on major histocompatibility complex (MHC) I molecules, which causes rapid antigen-specific naïve CD8 T-cell retention in the liver but not in other organs. Using bone-marrow chimeras and a novel transgenic mouse model (Tie2-H-2K(b) mice) with endothelial cell-specific MHC I expression, we provide evidence that cross-presentation by organ-resident and radiation-resistant LSECs in vivo was both essential and sufficient to cause antigen-specific retention of naïve CD8 T-cells under noninflammatory conditions. This was followed by sustained CD8 T-cell proliferation and expansion in vivo, but ultimately led to the development of T-cell tolerance.
Our results show that cross-presentation of circulating antigens by LSECs caused antigen-specific retention of naïve CD8 T-cells and identify antigen-specific T-cell adhesion as the first step in the induction of T-cell tolerance.
外周CD8 T细胞耐受性可在肝脏的淋巴外组织中产生，但导致肝细胞群体与循环T细胞发生耐受性相互作用的事件过程仍在很大程度上不明确。在此，我们证明，系统性循环抗原优先被小鼠肝窦内皮细胞（LSEC）摄取，而非肝脏或脾脏中的其他抗原呈递细胞，这导致抗原在主要组织相容性复合体（MHC）I分子上的交叉呈递，从而使抗原特异性初始CD8 T细胞快速滞留于肝脏而非其他器官。利用骨髓嵌合体和一种具有内皮细胞特异性MHC I表达的新型转基因小鼠模型（Tie2-H-2K(b)小鼠），我们提供证据表明，在非炎症条件下，体内器官驻留且抗辐射的LSEC进行的交叉呈递对于导致初始CD8 T细胞的抗原特异性滞留既是必要的也是充分的。随后，CD8 T细胞在体内持续增殖和扩增，但最终导致T细胞耐受性的形成。
我们的结果表明，LSEC对循环抗原的交叉呈递导致了初始CD8 T细胞的抗原特异性滞留，并确定抗原特异性T细胞黏附是诱导T细胞耐受性的第一步。
