Front. Immunol. Frontiers in Immunology Front. Immunol. 1664-3224 Frontiers Media S.A. 10.3389/fimmu.2016.00276 Immunology General Commentary Helios Should Not Be Cited as a Marker of Human Thymus-Derived Tregs. Commentary: Helios+ and Helios− Cells Coexist within the Natural FOXP3+ T Regulatory Cell Subset in Humans Elkord Eyad 1 2 3 4 * 1Cancer Center, Qatar Biomedical Research Institute, College of Science and Engineering, Hamad Bin Khalifa University, Qatar Foundation, Doha, Qatar 2College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates 3Biomedical Research Center, School of Environment and Life Sciences, University of Salford, Salford, UK 4Institute of Cancer Sciences, University of Manchester, Manchester, UK

Edited by: Stephen Paul Cobbold, University of Oxford, UK

Reviewed by: Wayne Hancock, Perelman School of Medicine at the University of Pennsylvania, USA

 *Correspondence: Eyad Elkord, eelkord@uaeu.ac.ae, e.elkord@salford.ac.uk, eyad.elkord@manchester.ac.uk

Specialty section: This article was submitted to Immunological Tolerance, a section of the journal Frontiers in Immunology

 08 07 2016 2016 7 276 06 06 2016 01 07 2016 Copyright © 2016 Elkord. 2016 Elkord

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 A commentary on Helios+ and Helios− Cells Coexist within the Natural FOXP3+ T Regulatory Cell Subset in Humans by Himmel ME, MacDonald KG, Garcia RV, Steiner TS, Levings MK. J Immunol (2013) 190:2001–8. doi: 10.4049/jimmunol.1390018 T regulatory cells Foxp3 Helios tTregs pTregs

Thymus-derived Tregs (tTregs) mediate peripheral tolerance, which benefits the host by controlling inflammation and preventing autoimmunity, whereas peripherally induced Tregs (pTregs) mediate tumor-induced suppression, which hurts the host by suppressing beneficial anti-tumor immunity (1–4). In 2010, Dr. Shevach’s group reported that Helios expression discriminates tTregs from pTregs (5). This work generated a lot of excitement due to the real need for markers to discriminate the good tTregs from the bad pTregs. This is of particular importance to specifically target pTregs to enhance anti-tumor immunity, while reserving tTregs to avoid provoking autoimmune diseases. Soon after, this work was questioned, and several studies showed that Helios can be induced in Foxp3+ T cells (6). A great wealth of recent studies excludes the value of Helios as a marker of tTregs. For example, a strong Helios expression can be induced in pTregs (7), and Helios expression is a marker of T cell activation and proliferation (8). Furthermore, it was confirmed that both Helios+/− subsets coexist within human FoxP3+ tTreg (9). A more recent study showed that neither Helios nor Neuropilin-1 expressions could identify Tregs of thymic or peripheral origin (10).

Regarding Helios function, Helios regulates Treg functional stability by inducing epigenetic silencing of IL-2 expression, and loss of Helios expression in Tregs enhanced expression of the IL-2 gene resulting in increased Treg proliferation and secretion of IL-2 following activation, as well as impaired suppressive activity (11). A more recent study by Dr. Shevach’s group reported that Helios controls some aspects of Treg-suppressive function (12). Interestingly, impairing Helios expression in Foxp3+ Tregs results in defective Tregs, and Helios is required for their stable inhibitory activity (13). Additionally, we found that Helios, and not FoxP3, is the marker of activated Tregs expressing immunosuppressive markers GARP/LAP (14).

Taken together, Helios expression confers stable phenotype of Tregs, and FoxP3+Helios+ Tregs have enhanced immunosuppressive characteristics, compared with FoxP3+Helios− Tregs (8, 15). Despite all these several recent studies confirmed that Helios is not a tTreg marker, unfortunately many studies cited/are still citing Helios as a tTreg marker. I believe that it is of great importance to make this very clear to avoid further confusion to the scientific community and not to cite Helios as a marker of tTregs anymore.

Author Contributions

The author conceived the idea and wrote the manuscript.

 Conflict of Interest Statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

 References Chaudhary B Abd Al Samid M al-Ramadi BK Elkord E. Phenotypic alterations, clinical impact and therapeutic potential of regulatory T cells in cancer. Expert Opin Biol Ther (2014) 14:931–45.10.1517/14712598.2014.90053924661020 Elkord E Alcantar-Orozco EM Dovedi SJ Tran DQ Hawkins RE Gilham DE. T regulatory cells in cancer: recent advances and therapeutic potential. Expert Opin Biol Ther (2010) 10:1573–86.10.1517/14712598.2010.52912620955112 Whiteside TL. What are regulatory T cells (Treg) regulating in cancer and why? Semin Cancer Biol (2012) 22:327–34.10.1016/j.semcancer.2012.03.00422465232 Whiteside TL. Induced regulatory T cells in inhibitory microenvironments created by cancer. Expert Opin Biol Ther (2014) 14:1411–25.10.1517/14712598.2014.92743224934899 Thornton AM Korty PE Tran DQ Wohlfert EA Murray PE Belkaid Y Expression of Helios, an Ikaros transcription factor family member, differentiates thymic-derived from peripherally induced Foxp3+ T regulatory cells. J Immunol (2010) 184:3433–41.10.4049/jimmunol.0904028 Elkord E. Comment on “Expression of Helios in peripherally induced Foxp3+ regulatory T cells”. J Immunol (2012) 189:500; author reply 1.10.4049/jimmunol.1290034 Gottschalk RA Corse E Allison JP. Expression of Helios in peripherally induced Foxp3+ regulatory T cells. J Immunol (2012) 188:976–80.10.4049/jimmunol.110296422198953 Akimova T Beier UH Wang L Levine MH Hancock WW. Helios expression is a marker of T cell activation and proliferation. PLoS One (2011) 6:e24226.10.1371/journal.pone.002422621918685 Himmel ME MacDonald KG Garcia RV Steiner TS Levings MK. Helios+ and Helios- cells coexist within the natural FOXP3+ T regulatory cell subset in humans. J Immunol (2013) 190:2001–8.10.4049/jimmunol.1201379 Szurek E Cebula A Wojciech L Pietrzak M Rempala G Kisielow P Differences in expression level of Helios and neuropilin-1 do not distinguish thymus-derived from extrathymically-induced CD4+Foxp3+ regulatory T cells. PLoS One (2015) 10:e0141161.10.1371/journal.pone.014116126495986 Baine I Basu S Ames R Sellers RS Macian F. Helios induces epigenetic silencing of IL2 gene expression in regulatory T cells. J Immunol (2013) 190:1008–16.10.4049/jimmunol.120079223275607 Sebastian M Lopez-Ocasio M Metidji A Rieder SA Shevach EM Thornton AM. Helios controls a limited subset of regulatory T cell functions. J Immunol (2016) 196(1):144–55.10.4049/jimmunol.150170426582951 Kim HJ Barnitz RA Kreslavsky T Brown FD Moffett H Lemieux ME Stable inhibitory activity of regulatory T cells requires the transcription factor Helios. Science (2015) 350:334–9.10.1126/science.aad061626472910 Elkord E Abd Al Samid M Chaudhary B. Helios, and not FoxP3, is the marker of activated Tregs expressing GARP/LAP. Oncotarget (2015) 6:20026–36.10.18632/oncotarget.477126343373 Zabransky DJ Nirschl CJ Durham NM Park BV Ceccato CM Bruno TC Phenotypic and functional properties of Helios+ regulatory T cells. PLoS One (2012) 7:e34547.10.1371/journal.pone.003454722479644