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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.

Intrahepatic lymphocytes have a distinct subset composition and phenotype. Compared with lymphoid tissues, the frequency of natural killer (NK) cells, NKT cells and gammadelta T cells among total lymphocytes is increased within the liver, and alphabeta T cells are predominantly effector/memory cells. Divergent hypotheses on the origin of intrahepatic T cells have emerged to explain this; in these hypotheses, either local development or selective recruitment of cells into the liver dominates. This Opinion highlights findings showing that the migratory preferences of lymphocyte subsets reflect their representation within the liver surprisingly well, suggesting that the composition of intrahepatic lymphocytes, in the absence of inflammation, is largely shaped by the dynamics of cell entry and exit into and from the liver.

Intrahepatic lymphocytes (IHL) differ phenotypically from cells found in the peripheral blood or in lymphoid organs. The liver contains T-cells that are also found in lymphoid organs but a higher proportion of these T-cells compared to those in lymphoid organs express activation or memory markers and very few naive T-cells are present within the liver. Furthermore, subsets such as NK and NK T-cells, which are detected at comparably lower levels within the lymphoid organs are increased within the liver. To investigate whether a preferential recruitment of certain lymphoid subsets from the circulation contributes to the composition of intrahepatic lymphocytes, we compared their frequency in the liver with their organ tropisms. CFSE-labeled murine lymphoid cells were injected intravenously and their distribution within liver and spleen was analyzed after 24 h. Especially CD45RBlow memory T-cells, NK and NK T-cells, which are also present at high proportions within IHL, became predominantly recruited into the liver. In contrast, subsets such as naive CD62Lhigh T-cells and B-cells, which are predominantly represented within the lymphoid organs, preferentially migrated into the spleen. These findings indicate that the pattern of migratory preferences reflects the representation of various subsets within the intrahepatic lymphocytes surprisingly well, suggesting that the composition of intrahepatic lymphocytes is largely shaped by the dynamics of entry and exit of cells into the organ.