title: Identification of a human Th1-like IFNγ-secreting Treg subtype deriving from effector T cells.
abstract: Characteristics and function of effector T-cells with regulatory properties (induced Treg, "iTreg") in humans are ill defined. Here we report that a proportion of activated, initially CD4(+)CD25(-)CD127(+) effector T-cells from human peripheral blood can convert into T-cells with regulatory activity while concomitantly secreting IFNγ. Upon short-term culture in vitro these cells expressed a panel of common Treg markers, including FOXP3, CD25, GITR, HLA-DR and CTLA-4 in parallel with the Th1-specific transcription factor T-bet. Despite their own IFNγ secretion they effectively suppressed IFNγ secretion in effector T cells in parallel with inhibition of their proliferation. Highly purified IFNγ(+)iTreg shared many functional properties with nTreg: Their suppressive activity was antigen-independent, contact-mediated and cytokine-independent. Of note, in contrast to nTreg an inhibitor of TGF-β1 signalling promoted the proliferation of IFNγ(+)iTreg, without abrogating their suppressive function. In addition in vivo in tonsils of patients with chronic tonsillitis an IFNγ-secreting subpopulation of the CD4(+)CD25(-)CD127(+)CD45RA(-) memory T helper cell population was detected, which exhibited regulatory properties as well. Our results support the existence of Th1-like adaptive Tregs in humans that express a robust regulatory phenotype, comparable to nTreg and at the same time share characteristics of Th1 cells. According to our in vitro data IFNγ(+)iTreg can emerge from activated effector T cells and downregulate Th1-mediated immune responses, supporting the hypothesis of effector T cell plasticity as a means for proper initiation and self regulation of inflammatory processes. This report characterizes a new subpopulation of human adaptive regulatory T-cells that derive from effector Th-cells and concomitantly express Th1-specific T-bet and IFNγ with Foxp3.
authors: Division of Rheumatology, University of Heidelberg, 69120 Heidelberg, Germany. ramkumar.venigalla@babraham.ac.uk
authors: Ram Kumar Chowdary
authors: RK
authors: Venigalla
authors: Padmaja Jayathi
authors: PJ
authors: Guttikonda
authors: Volker
authors: V
authors: Eckstein
authors: Anthony D
authors: AD
authors: Ho
authors: Serkan
authors: S
authors: Sertel
authors: Hanns-Martin
authors: HM
authors: Lorenz
authors: Theresa
authors: T
authors: Tretter
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D015415:Biomarkers / Q000378:metabolism; D002450:Cell Communication / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D002908:Chronic Disease; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007111:Immunity, Cellular; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000145:classification / Q000276:immunology* / Q000378:metabolism; D014069:Tonsillitis / Q000235:genetics / Q000276:immunology* / Q000473:pathology
chemical_list: D015703:Antigens, CD; D015415:Biomarkers; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007371:Interferon-gamma