Tolerance to apoptotic cells is regulated by indoleamine 2,3-dioxygenase

Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3909-14. doi: 10.1073/pnas.1117736109. Epub 2012 Feb 21.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Autoimmunity
  • Cytokines / metabolism
  • DNA / metabolism
  • Dendritic Cells / cytology
  • Female
  • Immune System
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / pharmacology*
  • Inflammation
  • Macrophages / metabolism
  • Membrane Glycoproteins / biosynthesis
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, Immunologic / biosynthesis
  • Sialic Acid Binding Ig-like Lectin 1
  • Spleen / cytology

Substances

  • Cytokines
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Membrane Glycoproteins
  • Receptors, Immunologic
  • Sialic Acid Binding Ig-like Lectin 1
  • Siglec1 protein, mouse
  • DNA