title: Human regulatory T cells control TCR signaling and susceptibility to suppression in CD4+ T cells.
abstract: Human CD4(+)CD25(hi)FOXP3(+) regulatory T cells maintain immunologic tolerance and prevent autoimmune and inflammatory immune responses. Regulatory T cells undergo a similar activation cycle as conventional CD4(+) T cells upon antigen stimulation. Here, we demonstrate that T cell receptors and costimulation are required to activate the regulatory T cell suppressive function. Regulatory T cells suppressed the T cell receptor signaling in effector T cells in a time-dependent manner that corresponded with inhibition of cytokine production and proliferation. Modulation of the activation level and thereby the suppressive capacity of regulatory T cells imposed distinct T cell receptor signaling signatures and hyporesponsiveness in suppressed and proliferating effector T cells and established a threshold for effector T cell proliferation. The immune suppression of effector T cells was completely reversible upon removal of regulatory T cells. However, the strength of prior immune suppression by regulatory T cells and corresponding T cell receptor signaling in effector T cells determined the susceptibility to suppression upon later reexposure to regulatory T cells. These findings demonstrate how the strength of the regulatory T cell suppressive function determines intracellular signaling, immune responsiveness, and the later susceptibility of effector T cells to immune suppression and contribute to unveiling the complex interactions between regulatory T cells and effector T cells.
authors.affiliation: Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Norway; Biotechnology Centre, University of Oslo, Norway; K.G. Jebsen Inflammation Research Centre, University of Oslo, Norway; K.G. Jebsen Centre for Cancer Immunotherapy, University of Oslo, Norway;
authors.forename: Stalin
authors.initials: S
authors.lastname: Chellappa
authors.affiliation: Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Norway; Biotechnology Centre, University of Oslo, Norway; K.G. Jebsen Inflammation Research Centre, University of Oslo, Norway; K.G. Jebsen Centre for Cancer Immunotherapy, University of Oslo, Norway;
authors.forename: Nora V
authors.initials: NV
authors.lastname: Lieske
authors.affiliation: Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Norway; Biotechnology Centre, University of Oslo, Norway; K.G. Jebsen Inflammation Research Centre, University of Oslo, Norway; Section for Transplantation Surgery Oslo University Hospital, Oslo, Norway; and.
authors.forename: Morten
authors.initials: M
authors.lastname: Hagness
authors.affiliation: Section for Transplantation Surgery Oslo University Hospital, Oslo, Norway; and.
authors.forename: Pål D
authors.initials: PD
authors.lastname: Line
authors.affiliation: Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Norway; Biotechnology Centre, University of Oslo, Norway; K.G. Jebsen Inflammation Research Centre, University of Oslo, Norway; K.G. Jebsen Centre for Cancer Immunotherapy, University of Oslo, Norway; Department of Infectious Diseases, Oslo University Hospital, Oslo, Norway kjetil.tasken@ncmm.uio.no.
authors.forename: Kjetil
authors.initials: K
authors.lastname: Taskén
authors.affiliation: Centre for Molecular Medicine Norway, Nordic EMBL Partnership, University of Oslo and Oslo University Hospital, Norway; Biotechnology Centre, University of Oslo, Norway; K.G. Jebsen Inflammation Research Centre, University of Oslo, Norway; Section for Transplantation Surgery Oslo University Hospital, Oslo, Norway; and e.m.aandahl@biotek.uio.no.
authors.forename: Einar M
authors.initials: EM
authors.lastname: Aandahl
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007165:Immunosuppression Therapy; D008213:Lymphocyte Activation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D016207:Cytokines; D011948:Receptors, Antigen, T-Cell
keywords: Teff proliferation; Treg; cell surface markers