Tolerance to self-antigens present in apoptotic cells is critical to maintain immune-homeostasis and prevent systemic autoimmunity. However, mechanisms that sustain self-tolerance are poorly understood. Here we show that systemic administration of apoptotic cells to mice induced splenic expression of the tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase (IDO). IDO expression was confined to the splenic marginal zone and was abrogated by depletion of CD169 + cells. Pharmacologic inhibition of IDO skewed the immune response to apoptotic cells, resulting in increased proinflammatory cytokine production and increased effector T-cell responses toward apoptotic cell-associated antigens. Presymptomatic lupus-prone MRL lpr/lpr mice exhibited abnormal elevated IDO expression in the marginal zone and red pulp and inhibition of IDO markedly accelerated disease progression. Moreover, chronic exposure of IDO-deficient mice to apoptotic cells induced a lupus-like disease with serum autoreactivity to double-stranded DNA associated with renal pathology and increased mortality. Thus, IDO limits innate and adaptive immunity to apoptotic self-antigens and IDO-mediated regulation inhibits inflammatory pathology caused by systemic autoimmune disease.inflammation | macrophage M acrophages (MΦ) are innate scavenging cells that are important in maintenance of tolerance to self. Mechanistically, it is unknown how MΦs contribute to self-tolerance although it is evident that clearance is necessary and must lead to regulation rather than adaptive immunity. In this vein it has been shown that interaction of apoptotic cells with MΦs results in the induction of an anti-inflammatory response dominated by TGF-β, which suppresses proinflammatory cytokine production (1, 2). However, the molecular mechanisms by which capture of apoptotic cells trigger immune suppression in vivo is unknown. Moreover, known mechanisms, such as exposure of phosphatidyl serine and TGF-β production, do not explain how tolerance is maintained at the molecular level.Apoptotic cells in circulation are trapped and removed in the marginal zone (MZ) of the spleen (3). The MZ is populated by specialized MΦs tightly associated with the reticular meshwork. These MΦ are defined by constitutive expression of either the scavenger macrophage receptor with collagenous structure, MARCO, or the metallophillic macrophage marker, MOMA-1 (4-6). The importance of MZ MΦs (MZMs) in apoptotic cell removal and tolerance was illustrated by our recent findings that their depletion significantly changed the immune response to apoptotic cells altering localization, increasing proinflammatory cytokine production, and enhancing phagocytosis and phagocyte activation (7). Similarly, in related studies deletion of MARCO + and MOMA-1 + MZMs retarded the clearance of apoptotic material and abrogated tolerance to apoptotic cell-associated antigens in a mouse model of experimental autoimmune encephalomyelitis (8). Thus, defective MZM-mediated apoptotic cell capture and removal appears to have sig...