Helios, and not FoxP3, is the marker of activated Tregs expressing GARP/LAP.
Regulatory T cells (Tregs) are key players of immune regulation/dysregulation both in physiological and pathophysiological settings. Despite significant advances in understanding Treg function, there is still a pressing need to define reliable and specific markers that can distinguish different Treg subpopulations. Herein we show for the first time that markers of activated Tregs [latency associated peptide (LAP) and glycoprotein A repetitions predominant (GARP, or LRRC32)] are expressed on CD4+FoxP3- T cells expressing Helios (FoxP3-Helios+) in the steady state. Following TCR activation, GARP/LAP are up-regulated on CD4+Helios+ T cells regardless of FoxP3 expression (FoxP3+/-Helios+). We show that CD4+GARP+/-LAP+ Tregs make IL-10 immunosuppressive cytokine but not IFN-γ effector cytokine. Further characterization of FoxP3/Helios subpopulations showed that FoxP3+Helios+ Tregs proliferate in vitro significantly less than FoxP3+Helios- Tregs upon TCR stimulation. Unlike FoxP3+Helios- Tregs, FoxP3+Helios+ Tregs secrete IL-10 but not IFN-γ or IL-2, confirming they are bona fide Tregs with immunosuppressive characteristics. Taken together, Helios, and not FoxP3, is the marker of activated Tregs expressing GARP/LAP, and FoxP3+Helios+ Tregs have more suppressive characteristics, compared with FoxP3+Helios- Tregs. Our work implies that therapeutic modalities for treating autoimmune and inflammatory diseases, allergies and graft rejection should be designed to induce and/or expand FoxP3+Helios+ Tregs, while therapies against cancers or infectious diseases should avoid such expansion/induction.
College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.|Biomedical Research Centre, School of Environment & Life Sciences, University of Salford, Manchester, United Kingdom.|Institutes of Cancer, Inflammation & Repair, University of Manchester, Manchester, United Kingdom.
Eyad
E
Elkord
College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates.|Biomedical Research Centre, School of Environment & Life Sciences, University of Salford, Manchester, United Kingdom.
May
M
Abd Al Samid
Biomedical Research Centre, School of Environment & Life Sciences, University of Salford, Manchester, United Kingdom.|University of Cambridge, Cambridge, United Kingdom.
Belal
B
Chaudhary
D022782:CCAAT-Enhancer-Binding Protein-beta / Q000096:biosynthesis / Q000097:blood / Q000276:immunology*; D002478:Cells, Cultured; D051858:Forkhead Transcription Factors / Q000097:blood / Q000276:immunology*; D006801:Humans; D051740:Ikaros Transcription Factor / Q000097:blood / Q000276:immunology*; D016753:Interleukin-10 / Q000096:biosynthesis / Q000097:blood / Q000276:immunology; D008213:Lymphocyte Activation; D008565:Membrane Proteins / Q000096:biosynthesis / Q000097:blood / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
D022782:CCAAT-Enhancer-Binding Protein-beta; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C111431:IKZF2 protein, human; C508609:IL10 protein, human; C087215:LRRC32 protein, human; D008565:Membrane Proteins; D016753:Interleukin-10; D051740:Ikaros Transcription Factor
FoxP3; GARP/LAP; Helios; Immune response; Immunity; Immunology and Microbiology Section; regulatory T cells