General Commentary ARTICLE
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
- 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
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
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.
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.
1. 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. doi:10.1517/14712598.2014.900539
2. 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. doi:10.1517/14712598.2010.529126
5. Thornton AM, Korty PE, Tran DQ, Wohlfert EA, Murray PE, Belkaid Y, et al. 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. doi:10.4049/jimmunol.0904028
9. 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. doi:10.4049/jimmunol.1201379
10. Szurek E, Cebula A, Wojciech L, Pietrzak M, Rempala G, Kisielow P, et al. 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. doi:10.1371/journal.pone.0141161
12. 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. doi:10.4049/jimmunol.1501704
13. Kim HJ, Barnitz RA, Kreslavsky T, Brown FD, Moffett H, Lemieux ME, et al. Stable inhibitory activity of regulatory T cells requires the transcription factor Helios. Science (2015) 350:334–9. doi:10.1126/science.aad0616
Keywords: T regulatory cells, Foxp3, Helios, tTregs, pTregs
Citation: Elkord E (2016) 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. Front. Immunol. 7:276. doi: 10.3389/fimmu.2016.00276
Received: 06 June 2016; Accepted: 01 July 2016;
Published: 08 July 2016
Edited by:Stephen Paul Cobbold, University of Oxford, UK
Reviewed by:Wayne Hancock, Perelman School of Medicine at the University of Pennsylvania, USA
Copyright: © 2016 Elkord. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.