Immune regulation by apoptotic cell clearance.

Apoptotic cell clearance by phagocytes is essential for the maintenance of self-tolerance under physiological conditions. Consistent with this, the intravenous injection of apoptotic cells can induce cell-associated antigen-specific immunosuppression or tolerance. The intravenous injection of apoptotic cells expressed a fragment of myelin oligodendrocyte glycoprotein (MOG)-induced MOG-specific T cell tolerance and suppressed the development of experimental autoimmune encephalomyelitis. However, the suppressive effects of the MOG-expressing apoptotic cells were largely eliminated by masking phosphatidylserine (PS) exposed on the apoptotic cells, suggesting that the PS-dependent engulfment of apoptotic cells is required for the tolerance induction. We found that this mechanism of tolerance induction requires the contribution of two cell populations in the splenic marginal zone (MZ). The MZ contains two types of macrophages: marginal metallophilic macrophages and MZ macrophages. These macrophages contribute to the rapid clearance of cell corpses in blood flow. In addition, we also found that CD8α(+), CD103(+) dendritic cells localizing in the MZ selectively phagocytose blood-borne dead cells and subsequently present dead cell-associated antigens to induce antigen-specific immunosuppression or tolerance.