Identification of a human Th1-like IFNγ-secreting Treg subtype deriving from effector T cells

• Published in: Journal of autoimmunity 2012-12, Vol.39 (4), p.377-387
• Main Authors: Chowdary Venigalla, Ram Kumar, Guttikonda, Padmaja Jayathi, Eckstein, Volker, Ho, Anthony D, Sertel, Serkan, Lorenz, Hanns-Martin, Tretter, Theresa
• Format: Article
• Language: English
• Subjects: Adaptive Treg; Allergy and Immunology; Antigens, CD - genetics; Antigens, CD - immunology; Biological and medical sciences; Biomarkers - metabolism; CD25 antigen; Cell Communication - genetics; Cell Communication - immunology; Cell culture; Cell Differentiation - immunology; Cell Proliferation; Cells, Cultured; Chronic Disease; CTLA-4 protein; Data processing; Effector cells; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - immunology; Foxp3 protein; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression Regulation - immunology; Helper cells; Histocompatibility antigen HLA; Humans; IFN-gamma; Immune regulation; Immunity, Cellular; Immunologic Memory; Inflammation; Interferon-gamma - genetics; Interferon-gamma - immunology; Lymphocyte Activation; Lymphocytes T; Peripheral blood; Signal Transduction; T helper cells; T-Lymphocytes, Helper-Inducer - immunology; T-Lymphocytes, Helper-Inducer - metabolism; T-Lymphocytes, Regulatory - classification; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Th1; Tonsillitis; Tonsillitis - genetics; Tonsillitis - immunology; Tonsillitis - pathology; Transcription factors; Transforming growth factor- beta 1
• ISSN: 0896-8411; 1095-9157
• DOI: 10.1016/j.jaut.2012.06.004

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.