title: NADH oxidase-dependent CD39 expression by CD8(+) T cells modulates interferon gamma responses via generation of adenosine.
abstract: Interferon gamma (IFNγ)-producing CD8(+) T cells (Tc1) play important roles in immunological disease. We now report that CD3/CD28-mediated stimulation of CD8(+) T cells to generate Tc1 cells, not only increases IFNγ production but also boosts the generation of reactive oxygen species (ROS) and augments expression of CD39. Inhibition of NADPH oxidases or knockdown of gp91phox in CD8(+) T cells abrogates ROS generation, which in turn modulates JNK and NFκB signalling with decreases in both IFNγ levels and CD39 expression. CD39(+)CD8(+) T cells substantially inhibit IFNγ production by CD39(-)CD8(+) T cells via the paracrine generation of adenosine, which is operational via adenosine type 2A receptors. Increases in numbers of CD39(+)CD8(+) T cells and associated enhancements in ROS signal transduction are noted in cells from patients with Crohn's disease. Our findings provide insights into Tc1-mediated IFNγ responses and ROS generation and link these pathways to CD39/adenosine-mediated effects in immunological disease.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts 02215, USA.
authors.forename: Aiping
authors.initials: A
authors.lastname: Bai
authors.affiliation: Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts 02215, USA.
authors.forename: Alan
authors.initials: A
authors.lastname: Moss
authors.affiliation: Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts 02215, USA.
authors.forename: Sonja
authors.initials: S
authors.lastname: Rothweiler
authors.affiliation: Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts 02215, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Serena Longhi
authors.affiliation: Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts 02215, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Department of Surgery, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts 02215, USA.
authors.forename: Wolfgang G
authors.initials: WG
authors.lastname: Junger
authors.affiliation: Division of Gastroenterology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard University, Boston, Massachusetts 02215, USA.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
mesh_terms: D000241:Adenosine / Q000378:metabolism*; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism; D001081:Apyrase / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D018106:CD28 Antigens; D017252:CD3 Complex; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D003106:Colon / Q000166:cytology / Q000276:immunology*; D003424:Crohn Disease / Q000276:immunology*; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents; D007371:Interferon-gamma / Q000276:immunology* / Q000378:metabolism; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000276:immunology* / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000276:immunology* / Q000378:metabolism; D019255:NADPH Oxidases / Q000276:immunology* / Q000378:metabolism; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D017382:Reactive Oxygen Species; D018047:Receptors, Purinergic P1 / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult
chemical_list: D015703:Antigens, CD; D018106:CD28 Antigens; D017252:CD3 Complex; D007166:Immunosuppressive Agents; D009097:Multienzyme Complexes; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D018047:Receptors, Purinergic P1; D007371:Interferon-gamma; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases; D001081:Apyrase; C067869:CD39 antigen; D000241:Adenosine