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
- 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. 10.1517/14712598.2014.900539 [DOI] [PubMed] [Google Scholar]
- 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. 10.1517/14712598.2010.529126 [DOI] [PubMed] [Google Scholar]
- 3.Whiteside TL. What are regulatory T cells (Treg) regulating in cancer and why? Semin Cancer Biol (2012) 22:327–34. 10.1016/j.semcancer.2012.03.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Whiteside TL. Induced regulatory T cells in inhibitory microenvironments created by cancer. Expert Opin Biol Ther (2014) 14:1411–25. 10.1517/14712598.2014.927432 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. 10.4049/jimmunol.0904028 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.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 [DOI] [PubMed] [Google Scholar]
- 7.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.1102964 [DOI] [PubMed] [Google Scholar]
- 8.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.0024226 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. 10.4049/jimmunol.1201379 [DOI] [PubMed] [Google Scholar]
- 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. 10.1371/journal.pone.0141161 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.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.1200792 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. 10.4049/jimmunol.1501704 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 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. 10.1126/science.aad0616 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.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.4771 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.Zabransky DJ, Nirschl CJ, Durham NM, Park BV, Ceccato CM, Bruno TC, et al. Phenotypic and functional properties of Helios+ regulatory T cells. PLoS One (2012) 7:e34547. 10.1371/journal.pone.0034547 [DOI] [PMC free article] [PubMed] [Google Scholar]