Bertolino Patrick, Schrage Arnhild, Bowen David G, Klugewitz Katja, Ghani Saeed, Eulenburg Katharina, Holz Lauren, Hogg Nancy, McCaughan Geoffrey W, Hamann Alf
AW Morrow Gastroenterology and Liver Centre & Centenary Institute of Cancer Medicine and Cell Biology, Royal Prince Alfred Hospital, University of Sydney, Newtown, NSW, Australia.
Hepatology. 2005 Nov;42(5):1063-71. doi: 10.1002/hep.20885.
We have previously shown that naïve CD8+ T cells recognizing their cognate antigen within the liver are retained and undergo activation in situ, independent from lymphoid tissues. Intrahepatic primary T cell activation results in apoptosis and may play a crucial role in the ability of the liver to induce tolerance. Although adhesion molecules required for intrahepatic retention of T cells that have undergone previous extra-hepatic activation have been characterized, adhesive interactions involved in selective antigen-dependent intrahepatic retention of naïve CD8+ T cells have not been investigated. By adoptively transferring radiolabeled T cell receptor (TCR)-transgenic CD8+ T cells into recipient animals ubiquitously expressing the relevant antigen, we show that 40% to 60 % of donor antigen-specific naïve CD8+ T cells were retained in the liver within 1 hour after transfer, despite ubiquitous expression of the antigen. Intravital microscopy showed that most donor naïve T cells slowed down and were irreversibly retained intrahepatically within the first few minutes after adoptive transfer, strongly suggesting that they were directly activated by liver cells in situ. This process was largely dependent on LFA-1 and ICAM-1, but was independent of blocking with antibodies against VCAM-1, alpha4 integrin, P-selectin, VAP-1, and beta1 integrin. ICAM-2 seemed to play only a minor role in this process. Interestingly, LFA-1 expressed by both donor T cells and liver cells was involved in retention of the antigen-reactive T cells. In conclusion, LFA-1-dependent intrahepatic T cell retention and activation are linked events that may play a crucial role in the establishment of liver-induced antigen-specific tolerance.
我们之前已经表明，在肝脏内识别其同源抗原的初始CD8⁺ T细胞会被保留并在原位发生激活，这一过程独立于淋巴组织。肝内原发性T细胞激活会导致细胞凋亡，并且可能在肝脏诱导耐受的能力中发挥关键作用。尽管已经对先前在肝外激活的T细胞在肝内保留所需的黏附分子进行了表征，但尚未研究参与初始CD8⁺ T细胞选择性抗原依赖性肝内保留的黏附相互作用。通过将放射性标记的T细胞受体（TCR）转基因CD8⁺ T细胞过继转移到普遍表达相关抗原的受体动物中，我们发现，尽管抗原普遍表达，但40%至60%的供体抗原特异性初始CD8⁺ T细胞在转移后1小时内被保留在肝脏中。活体显微镜检查显示，大多数供体初始T细胞在过继转移后的最初几分钟内速度减慢并不可逆地保留在肝内，这强烈表明它们在原位被肝细胞直接激活。这一过程在很大程度上依赖于淋巴细胞功能相关抗原-1（LFA-1）和细胞间黏附分子-1（ICAM-1），但与抗血管细胞黏附分子-1（VCAM-1）、α4整合素、P-选择素、血管黏附蛋白-1（VAP-1）和β1整合素的抗体阻断无关。ICAM-2似乎在这一过程中仅起次要作用。有趣的是，供体T细胞和肝细胞表达的LFA-1都参与了抗原反应性T细胞的保留。总之，依赖LFA-1的肝内T细胞保留和激活是相关事件，可能在肝脏诱导的抗原特异性耐受的建立中起关键作用。
