title: Myeloid suppressor lines inhibit T cell responses by an NO-dependent mechanism.
abstract: CD11b(+)Gr-1(+) myeloid suppressor cells (MSC) accumulate in lymphoid organs under conditions of intense immune stress where they inhibit T and B cell function. We recently described the generation of immortalized MSC lines that provide a homogeneous source of suppressor cells for dissecting the mechanism of suppression. In this study we show that the MSC lines potently block in vitro proliferation of T cells stimulated with either mitogen or antigenic peptide, with as few as 3% of MSC cells causing complete suppression. Inhibition of mitogenic and peptide-specific responses is not associated with a loss in IL-2 production or inability to up-modulate the early activation markers, CD69 and CD25, but results in direct impairment of the three IL-2R signaling pathways, as demonstrated by the lack of Janus kinase 3, STAT5, extracellular signal-regulated kinase, and Akt phosphorylation in response to IL-2. Suppression is mediated by and requires NO, which is secreted by MSC in response to signals from activated T cells, including IFN-gamma and a contact-dependent stimulus. Experiments with inducible NO synthase knockout mice demonstrated that the inhibition of T cell proliferation by CD11b(+)Gr-1(+) cells in the spleens of immunosuppressed mice is also dependent upon NO, indicating that the MSC lines accurately represent their normal counterparts. The distinctive capacity of MSC to generate suppressive signals when encountering activated T cells defines a specialized subset of myeloid cells that most likely serve a regulatory function during times of heightened immune activity.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892. Department of Oncology and Surgical Sciences, Oncology Section, Azienda Ospedaliera, Padova, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Mazzoni
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bronte
authors.forename: Alberto
authors.initials: A
authors.lastname: Visintin
authors.forename: Jessica H
authors.initials: JH
authors.lastname: Spitzer
authors.forename: Elisa
authors.initials: E
authors.lastname: Apolloni
authors.forename: Paolo
authors.initials: P
authors.lastname: Serafini
authors.forename: Paola
authors.initials: P
authors.lastname: Zanovello
authors.forename: David M
authors.initials: DM
authors.lastname: Segal
mesh_terms: D000818:Animals; D002450:Cell Communication / Q000276:immunology; D002460:Cell Line; D002461:Cell Line, Transformed; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D016130:Immunophenotyping; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000502:physiology; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D009569:Nitric Oxide / Q000494:pharmacology / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D004791:Enzyme Inhibitors; D007376:Interleukin-2; D016177:Macrophage-1 Antigen; D009569:Nitric Oxide; D007371:Interferon-gamma; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse