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Dendritic Cells Induce a Subpopulation of IL-12Rβ2-Expressing Treg that Specifically Consumes IL-12 to Control Th1 Responses

 Uri Sela  ;  Chae Gyu Park  ;  Andrew Park  ;  Peter Olds  ;  Shu Wang  ;  Ralph M. Steinman  ;  Vincent A. Fischetti 
 PLOS ONE, Vol.11(1) : e0146412, 2016 
Journal Title
Issue Date
Animals ; Biological Transport ; Cell Differentiation ; Cell Lineage/genetics ; Cell Lineage/immunology* ; Cell Proliferation ; Dendritic Cells/cytology* ; Dendritic Cells/immunology ; Female ; Gene Expression Regulation ; Immunophenotyping ; Interleukin-12/genetics* ; Interleukin-12/immunology ; Interleukin-6/genetics ; Interleukin-6/immunology ; Lymphocyte Culture Test, Mixed ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/immunology ; Mice ; Mice, Inbred BALB C ; Receptors, Interleukin-12/genetics* ; Receptors, Interleukin-12/immunology ; Signal Transduction ; T-Lymphocytes, Regulatory/cytology* ; T-Lymphocytes, Regulatory/immunology ; Th1 Cells/cytology* ; Th1 Cells/immunology ; Th1-Th2 Balance ; Toll-Like Receptor 7/genetics ; Toll-Like Receptor 7/immunology ; Toll-Like Receptor 8/genetics ; Toll-Like Receptor 8/immunology ; Tumor Necrosis Factor-alpha/genetics ; Tumor Necrosis Factor-alpha/immunology
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.
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1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
Yonsei Authors
Park, Chae Gyu(박채규) ORCID logo https://orcid.org/0000-0003-1906-1308
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