title: Unified immune modulation by 4-1BB triggering leads to diverse effects on disease progression in vivo.
abstract: 4-1BB (CD137) is a powerful T-cell costimulatory molecule in the treatment of virus infections and tumors, but recent studies have also uncovered regulatory functions of 4-1BB signaling. Since 4-1BB triggering suppresses autoimmunity by accumulating indoleamine 2,3-dioxygenase (IDO) in dendritic cells (DCs) in an interferon (IFN)-γ-dependent manner, we asked whether similar molecular and cellular changes were induced by 4-1BB triggering in virus-infected mice. 4-1BB triggering increased IFN-γ and IDO, and suppressed CD4(+) T cells, in C57BL/6 mice infected with the type 1 KOS strain of Herpes simplex virus (HSV-1), as it does in an autoimmune disease model. Detailed analysis of the CD4(+) T suppression showed that freshly activated CD62L(high) T cells underwent apoptosis in the early phase of suppression, and CD62L(low) effector/memory T cells in the later phase. Although 4-1BB triggering resulted in similar cellular changes - increased CD8(+) T and decreased CD4(+) T cells, it had different effects on mortality in mice infected with HSV-1 RE, influenza, and Japanese encephalitis virus (JEV); it increased mortality in influenza-infected mice but decreased it in JEV-infected mice. Since the dominant type of immune cell generated to protect the host was different for each virus - CD4(+) T cells and neutrophils in HSV-1 RE infection, both CD4(+) T and CD8(+) T cells in influenza infection, and a crucial role for B cells in JEV infection, 4-1BB triggering resulted in different therapeutic outcomes. We conclude that the therapeutic outcome of 4-1BB triggering is determined by whether the protective immunity generated against the virus was beneficially altered by the 4-1BB triggering.
authors.affiliation: Immune and Cell Therapy Branch, Division of Cancer Biology, R&D Center for Cancer Therapeutics, National Cancer Center, 809 Madu, Ilsan, Goyang, Kyeonggi-do 411-769, Republic of Korea.
authors.forename: Beom K
authors.initials: BK
authors.lastname: Choi
authors.forename: Young H
authors.initials: YH
authors.lastname: Kim
authors.forename: Jae H
authors.initials: JH
authors.lastname: Choi
authors.forename: Chang H
authors.initials: CH
authors.lastname: Kim
authors.forename: Kwang-Soon
authors.initials: KS
authors.lastname: Kim
authors.forename: Young-Chul
authors.initials: YC
authors.lastname: Sung
authors.forename: Young-Min
authors.initials: YM
authors.lastname: Lee
authors.forename: John R
authors.initials: JR
authors.lastname: Moffett
authors.forename: Byoung S
authors.initials: BS
authors.lastname: Kwon
mesh_terms: D053330:4-1BB Ligand / Q000276:immunology*; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D018450:Disease Progression; D004664:Encephalitis Virus, Japanese / Q000472:pathogenicity; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis / Q000276:immunology; D009980:Influenza A virus / Q000472:pathogenicity; D007371:Interferon-gamma / Q000096:biosynthesis; D019041:L-Selectin; D018655:Lymphocyte Count; D051379:Mice; D008807:Mice, Inbred BALB C / Q000821:virology; D008810:Mice, Inbred C57BL / Q000821:virology; D018345:Mice, Knockout; D015398:Signal Transduction / Q000276:immunology; D018139:Simplexvirus / Q000472:pathogenicity; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000276:immunology
chemical_list: D053330:4-1BB Ligand; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9; D019041:L-Selectin; D007371:Interferon-gamma