title: Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase.
abstract: 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.
authors.affiliation: Department of Medicine, and Immunotherapy Center, Georgia Health Sciences University, Augusta, GA 30912, USA.
authors.forename: Buvana
authors.initials: B
authors.lastname: Ravishankar
authors.forename: Haiyun
authors.initials: H
authors.lastname: Liu
authors.forename: Rahul
authors.initials: R
authors.lastname: Shinde
authors.forename: Phillip
authors.initials: P
authors.lastname: Chandler
authors.forename: Babak
authors.initials: B
authors.lastname: Baban
authors.forename: Masato
authors.initials: M
authors.lastname: Tanaka
authors.forename: David H
authors.initials: DH
authors.lastname: Munn
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Mellor
authors.forename: Mikael C I
authors.initials: MC
authors.lastname: Karlsson
authors.forename: Tracy L
authors.initials: TL
authors.lastname: McGaha
mesh_terms: D000818:Animals; D017209:Apoptosis; D015551:Autoimmunity; D016207:Cytokines / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology; D005260:Female; D007107:Immune System; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000494:pharmacology*; D007249:Inflammation; D008264:Macrophages / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011971:Receptors, Immunologic / Q000096:biosynthesis; D063267:Sialic Acid Binding Ig-like Lectin 1; D013154:Spleen / Q000166:cytology
chemical_list: D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008562:Membrane Glycoproteins; D011971:Receptors, Immunologic; D063267:Sialic Acid Binding Ig-like Lectin 1; C571167:Siglec1 protein, mouse; D004247:DNA