4-1BB-mediated amelioration of experimental autoimmune uveoretinitis is caused by indoleamine 2,3-dioxygenase-dependent mechanisms.
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.
Choi
Beom K
BK
The Immunomodulation Research Center, University of Ulsan, Ulsan 680-749, Republic of Korea.
Asai
Tatsuhiko
T
Vinay
Dass S
DS
Kim
Young H
YH
Kwon
Byoung S
BS
D053330:4-1BB Ligand; D000818:Animals; D001327:Autoimmune Diseases / Q000201:enzymology / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018845:CD11 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D049109:Cell Proliferation; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000037:antagonists & inhibitors / Q000378:metabolism; D012160:Retina / Q000378:metabolism* / Q000473:pathology*; D048069:Tumor Necrosis Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014602:Uvea / Q000378:metabolism* / Q000473:pathology*
D053330:4-1BB Ligand; D018845:CD11 Antigens; D004791:Enzyme Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; C505975:Tnfsf9 protein, mouse; D048069:Tumor Necrosis Factors; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II