Research Papers: Immunology:

Helios, and not FoxP3, is the marker of activated Tregs expressing GARP/LAP

Eyad Elkord _, May Abd Al Samid and Belal Chaudhary

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Oncotarget. 2015; 6:20026-20036. https://doi.org/10.18632/oncotarget.4771

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Eyad Elkord1,2,3, May Abd Al Samid1,2, Belal Chaudhary2,4

1College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates

2Biomedical Research Centre, School of Environment & Life Sciences, University of Salford, Manchester, United Kingdom

3Institutes of Cancer, Inflammation & Repair, University of Manchester, Manchester, United Kingdom

4University of Cambridge, Cambridge, United Kingdom

Correspondence to:

Eyad Elkord, e-mail: [email protected], [email protected], [email protected]

Keywords: Immunology and Microbiology Section, Immune response, Immunity, regulatory T cells, GARP/LAP, FoxP3, Helios

Received: May 13, 2015     Accepted: July 17, 2015     Published: July 30, 2015


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 (FoxP3Helios+) 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.

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