title: Nitric oxide controls an inflammatory-like Ly6C(hi)PDCA1+ DC subset that regulates Th1 immune responses.
abstract: Using NOS2 KO mice, we investigated the hypothesis that NO modulation of BM-DC contributes to the NO-mediated control of Th1 immune responses. BM-DCs from NOS2 KO mice, compared with WT BM-DCs, have enhanced survival and responsiveness to TLR agonists, develop more Ly6C(hi)PDCA1(+) DCs that resemble inflammatory DCs and produce high levels of inflammatory cytokines. Also, compared with WT-infected mice, NOS2 KO mice infected with WNV showed enhanced expansion of a similar inflammatory Ly6C(hi)PDCA1(+) DC subset. Furthermore, in contrast to WT DCs, OVA-loaded NOS2 KO BM-DCs promoted increased IFN-γ production by OTII CD4(+) T cells in vitro and when adoptively transferred in vivo. The addition of a NO donor to NOS2 KO BM-DCs prior to OTII T cells priming in vivo was sufficient to revert Th1 immune responses to levels induced by WT BM-DCs. Thus, autocrine NO effects on maturation of inflammatory DCs and on DC programming of T cells may contribute to the protective role of NO in autoimmune diseases and infections. Regulating NO levels may be a useful tool to shape beneficial immune responses for DC-based immunotherapy.
authors.affiliation: Department of Immunology, University of Washington, Box 357330, 1959 N.E. Pacific St., Seattle, WA 98195, USA. giordano@u.washington.edu
authors.forename: Daniela
authors.initials: D
authors.lastname: Giordano
authors.forename: Chang
authors.initials: C
authors.lastname: Li
authors.forename: Mehul S
authors.initials: MS
authors.lastname: Suthar
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Draves
authors.forename: Daphne Y
authors.initials: DY
authors.lastname: Ma
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
authors.forename: Edward A
authors.initials: EA
authors.lastname: Clark
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000378:metabolism*; D000954:Antigens, Surface / Q000378:metabolism*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D051940:B7-2 Antigen / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D015536:Down-Regulation; D000939:Epitopes / Q000276:immunology; D007109:Immunity / Q000276:immunology*; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D018836:Inflammation Mediators / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor; D018417:Th1 Cells / Q000276:immunology*; D051193:Toll-Like Receptors / Q000276:immunology; D015854:Up-Regulation; D014901:West Nile Fever / Q000276:immunology / Q000821:virology; D014902:West Nile virus / Q000502:physiology
chemical_list: D000950:Antigens, Ly; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D051940:B7-2 Antigen; D015415:Biomarkers; D016207:Cytokines; D000939:Epitopes; D018836:Inflammation Mediators; C494192:Ly-6C antigen, mouse; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D051193:Toll-Like Receptors; D009569:Nitric Oxide; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse