title: 4-1BB triggering ameliorates experimental autoimmune encephalomyelitis by modulating the balance between Th17 and regulatory T cells.
abstract: Agonistic anti-4-1BB Ab is known to ameliorate experimental autoimmune encephalomyelitis. 4-1BB triggering typically leads to the expansion of CD8(+) T cells, which produce abundant IFN-γ, and this in turn results in IDO-dependent suppression of autoimmune responses. However, because neutralization of IFN-γ or depletion of CD8(+) T cell only partially abrogates the effect of 4-1BB triggering, we sought to identify an additional mechanism of 4-1BB-triggered suppression of autoimmune responses using IFN-γ- or IFN-γR-deficient mice. 4-1BB triggering inhibited the generation of Th17 cells that is responsible for experimental autoimmune encephalomyelitis induction and progression, and increased Foxp3(+)CD4(+) regulatory T (Treg) cells, particularly among CD4(+) T cells. This was not due to a direct effect of 4-1BB signaling on CD4(+) T cell differentiation: 4-1BB signaling not only reduced Th17 cells and increased Treg cells in wild-type mice, which could be due to IFN-γ production by the CD8(+) T cells, but also did so in IFN-γ-deficient mice, in that case by downregulating IL-6 production. These results show that although secondary suppressive mechanisms evoked by 4-1BB triggering are usually masked by the strong effects of IFN-γ, 4-1BB signaling seems to modulate autoimmune responses by a number of mechanisms, and modulation of the Th17 versus Treg cell balance is one of those mechanisms.
authors.affiliation: Immune and Cell Therapy Branch, Division of Cancer Biology, National Cancer Center, Goyang-si, Gyeongi-do 410-769, Korea.
authors.forename: Young H
authors.initials: YH
authors.lastname: Kim
authors.forename: Beom K
authors.initials: BK
authors.lastname: Choi
authors.forename: Su M
authors.initials: SM
authors.lastname: Shin
authors.forename: Chang H
authors.initials: CH
authors.lastname: Kim
authors.forename: Ho S
authors.initials: HS
authors.lastname: Oh
authors.forename: Sang H
authors.initials: SH
authors.lastname: Park
authors.forename: Don G
authors.initials: DG
authors.lastname: Lee
authors.forename: Myoung J
authors.initials: MJ
authors.lastname: Lee
authors.forename: Kwang H
authors.initials: KH
authors.lastname: Kim
authors.forename: Dass S
authors.initials: DS
authors.lastname: Vinay
authors.forename: Byoung S
authors.initials: BS
authors.lastname: Kwon
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D018791:CD4 Lymphocyte Count; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D002478:Cells, Cultured; D018450:Disease Progression; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D007371:Interferon-gamma / Q000172:deficiency / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D000096743:Interferon gamma Receptor
chemical_list: D007371:Interferon-gamma; D017471:Receptors, Interferon; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D000096743:Interferon gamma Receptor