The liver mediates apoptotic cell-induced immune regulation

Allogeneic apoptotic cells have been demonstrated to induce allograft tolerance, but the mechanisms for this remain unclear. The study presented here investigates organs in which the tolerogenic immune responses may occur. Distribution of live or apoptotic CFSE(+) splenocytes in recipients' organs and phagocytosis by liver antigen-presenting cells (APC) were investigated by fluorescence microscopy and flow cytometry, and cytokine expression was analysed by Multiplex and ELISA. It was found that allogeneic or autogenic apoptotic cells preferentially accumulated in the liver within 30 min, peaked at 60 min, and disappeared at 12 h after infusion, whereas these cells scarcely appeared in the spleen. The accumulation in the liver was apoptotic cell-specific as both allogeneic and autogenic live splenocytes were completely deposited in the spleen. Liver phagocytes, including Kupffer cells, liver sinusoidal endothelial cells and dendritic cells, all efficiently phagocytized apoptotic cells in vitro and in vivo. Although a Th1 cytokine profile found both in the spleen and liver in the recipients of allogeneic apoptotic cells, a rapid and consistent Th2 cytokine profile specifically was initiated in the liver. From this, we conclude that liver APC phagocytize donor apoptotic cells and induce liver-specific Th2 cytokines, which may contribute to the mechanisms of allograft tolerance induced by donor apoptotic cells.