title: Dendritic Cells Induce a Subpopulation of IL-12Rβ2-Expressing Treg that Specifically Consumes IL-12 to Control Th1 Responses.
abstract: Cytokines secreted from dendritic cells (DCs) play an important role in the regulation of T helper (Th) cell differentiation and activation into effector cells. Therefore, controlling cytokine secretion from DCs may potentially regulate Th differentiation/activation. DCs also induce de-novo generation of regulatory T cells (Treg) that modulate the immune response. In the current study we used the mixed leukocyte reaction (MLR) to investigate the effect of allospecific Treg on IL-12, TNFα and IL-6 secretion by DCs. Treg cells were found to markedly down-regulate IL-12 secretion from DCs following stimulation with TLR7/8 agonist. This down-regulation of IL-12 was neither due to a direct suppression of its production by the DCs nor a result of marked DC death. We found that IL-12 was rather actively consumed by Treg cells. IL-12 consumption was mediated by a subpopulation of IL-12Rβ2-expressing Treg cells and was dependent on MHC class-II expressed on dendritic cells. Furthermore, IL-12 consumption by Tregs increased their suppressive effect on T cell proliferation and Th1 activation. These results provide a new pathway of Th1 response regulation where IL-12 secreted by DCs is consumed by a sub-population of IL-12Rβ2-expressing Treg cells. Consumption of IL-12 by Tregs not only reduces the availability of IL-12 to Th effector cells but also enhances the Treg immunosuppressive effect. This DC-induced IL-12Rβ2-expressing Treg subpopulation may have a therapeutic advantage in suppressing Th1 mediated autoimmunity.
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Chris Browne Center for Immunology and Immune Disease, The Rockefeller University, New York, NY, 10065, United States of America.|Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, NY, 10065, United States of America.
authors.forename: Uri
authors.initials: U
authors.lastname: Sela
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Chris Browne Center for Immunology and Immune Disease, The Rockefeller University, New York, NY, 10065, United States of America.|Laboratory of Immunology, Brain Korea 21 PLUS Project for Medical Science, Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
authors.forename: Chae Gyu
authors.initials: CG
authors.lastname: Park
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Chris Browne Center for Immunology and Immune Disease, The Rockefeller University, New York, NY, 10065, United States of America.
authors.forename: Andrew
authors.initials: A
authors.lastname: Park
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Chris Browne Center for Immunology and Immune Disease, The Rockefeller University, New York, NY, 10065, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Olds
authors.affiliation: Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, NY, 10065, United States of America.
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Laboratory of Cellular Physiology and Immunology, Chris Browne Center for Immunology and Immune Disease, The Rockefeller University, New York, NY, 10065, United States of America.
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Steinman
authors.affiliation: Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, New York, NY, 10065, United States of America.
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Fischetti
mesh_terms: D000818:Animals; D001692:Biological Transport; D002454:Cell Differentiation; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology*; D049109:Cell Proliferation; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation; D016130:Immunophenotyping; D018664:Interleukin-12 / Q000235:genetics* / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D053707:Receptors, Interleukin-12 / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology; D058408:Th1-Th2 Balance; D051199:Toll-Like Receptor 7 / Q000235:genetics / Q000276:immunology; D051200:Toll-Like Receptor 8 / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology
chemical_list: C508443:Il12rb2 protein, mouse; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D053707:Receptors, Interleukin-12; C552579:TLR8 protein, mouse; C477038:Tlr7 protein, mouse; D051199:Toll-Like Receptor 7; D051200:Toll-Like Receptor 8; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D018664:Interleukin-12