4-1BB-mediated amelioration of experimental autoimmune uveoretinitis is caused by indoleamine 2,3-dioxygenase-dependent mechanisms

Cytokine. 2006 Jun;34(5-6):233-42. doi: 10.1016/j.cyto.2006.04.008. Epub 2006 Aug 8.

Abstract

Interphotoreceptor retinoid binding protein (IRBP)-induced experimental autoimmune uveoretinitis (EAU) is a CD4+ T cell-mediated autoimmune disease. Development of EAU is inhibited by treatment with an agonistic anti-4-1BB mAb. Even established EAU was alleviated by anti-4-1BB mAb. However, inhibition of 4-1BB/4-1BB ligand (4-1BBL) interaction does not suppress the development of EAU. It appears that cross-linking of 4-1BB evokes an active antigen-specific suppression mechanism rather than merely blocking 4-1BB/4-1BBL interaction. We found that administration of anti-4-1BB mAb induced massive clonal expansion of CD11c+CD8+ T cells that produced IFN-gamma, resulting in accumulation of a high level of indoleamine 2,3-dioxygenase (IDO) in CD11c+ dendritic cells. 4-1BB-mediated suppression of EAU was reversed by the pharmacological IDO inhibitor, 1-methyl-tryptophan (1-MT). These studies demonstrate that suppression of EAU results from antigen-driven, 4-1BB-mediated expansion of novel CD11c+CD8+ T cells that suppress antigen-specific CD4+ T cells via an IDO-dependent mechanism.

Publication types

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

MeSH terms

  • 4-1BB Ligand
  • Animals
  • Autoimmune Diseases / enzymology
  • Autoimmune Diseases / genetics
  • Autoimmune Diseases / immunology
  • Autoimmune Diseases / metabolism*
  • CD11 Antigens / metabolism
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Proliferation
  • Disease Models, Animal
  • Enzyme Inhibitors / pharmacology
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism*
  • Inflammation / immunology
  • Inflammation / metabolism
  • Inflammation / pathology
  • Interferon-gamma / biosynthesis
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Nitric Oxide Synthase Type II / antagonists & inhibitors
  • Nitric Oxide Synthase Type II / metabolism
  • Retina / metabolism*
  • Retina / pathology*
  • Tumor Necrosis Factors / deficiency
  • Tumor Necrosis Factors / genetics
  • Tumor Necrosis Factors / immunology
  • Tumor Necrosis Factors / metabolism*
  • Uvea / metabolism*
  • Uvea / pathology*

Substances

  • 4-1BB Ligand
  • CD11 Antigens
  • Enzyme Inhibitors
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Tnfsf9 protein, mouse
  • Tumor Necrosis Factors
  • Interferon-gamma
  • Nitric Oxide Synthase Type II