title: Arginase-dependent suppression by CpG-ODN plus IFA-induced splenic myeloid CD11b(+)Gr1(+) cells.
abstract: The ability of synthetic oligodeoxynucleotides containing unmethylated cytosine guanine motifs (CpG-ODN) to induce both stimulatory and counter-regulatory responses offers novel opportunities for using these molecules as immunomodulatory agents in different therapeutic strategies. Here, we investigated the potential of CpG-ODN to activate the arginase (ARG) enzyme in vivo and focused on the consequences of this activation in T-cell proliferation. Challenging mice subcutaneously with CpG-ODN emulsified in incomplete Freund's adjuvant (IFA) induced ARG and reduced T-cell proliferation associated with CD3ζ chain downregulation. Interestingly, impaired T-cell expansion correlated with elevated levels of CD11b(+)Gr1(+) myeloid cells localized near T-cell areas in the spleen. In addition, purified CD11b(+) cells obtained from the spleen of CpG-ODN+IFA-treated mice exhibited increased ARG activity and ARG I expression along with an augmented [(3)H]-L-arginine uptake. CD11b(+) myeloid cells significantly suppressed T-cell proliferation and CD3ζ chain expression induced by a polyclonal stimulus. Furthermore, these effects could be recovered by the addition of excess L-arginine or by treatment of CD11b(+) cells with a specific ARG inhibitor. This study provides a novel evidence that CpG-ODN+IFA are able to induce splenic CD11b(+) cells with ARG activity, with this population being responsible for the impaired T-cell proliferation observed after the treatment with CpG-ODN+IFA. These results underscore a key role of CpG-ODN on ARG activity in vivo and add support to the growing body of evidence in favor of a counter-regulatory role for CpG-ODN in an immune response.
authors.affiliation: Centro de Investigación en Bioquímica Clínica e Inmunología, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
authors.forename: Romina P
authors.initials: RP
authors.lastname: Ranocchia
authors.forename: Carolina V
authors.initials: CV
authors.lastname: Gorlino
authors.forename: María I
authors.initials: MI
authors.lastname: Crespo
authors.forename: María F
authors.initials: MF
authors.lastname: Harman
authors.forename: Miriam V
authors.initials: MV
authors.lastname: Liscovsky
authors.forename: Gabriel
authors.initials: G
authors.lastname: Morón
authors.forename: Belkys A
authors.initials: BA
authors.lastname: Maletto
authors.forename: María C
authors.initials: MC
authors.lastname: Pistoresi-Palencia
mesh_terms: D000818:Animals; D001119:Arginase / Q000276:immunology* / Q000378:metabolism; D001120:Arginine / Q000378:metabolism; D039481:CD11b Antigen / Q000276:immunology / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D005620:Freund's Adjuvant / Q000276:immunology* / Q000494:pharmacology; D008055:Lipids / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018613:Microscopy, Confocal; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000276:immunology* / Q000494:pharmacology; D019707:Receptors, Chemokine / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014316:Tritium
chemical_list: D039481:CD11b Antigen; D017252:CD3 Complex; C121704:CD3 antigen, zeta chain; C408982:CPG-oligonucleotide; C503133:Gr-1 protein, mouse; D008055:Lipids; D009838:Oligodeoxyribonucleotides; D019707:Receptors, Chemokine; C114843:incomplete Freund's adjuvant; D014316:Tritium; D005620:Freund's Adjuvant; D001120:Arginine; D001119:Arginase