Helios distinguishes thymic-derived natural Tregs (nTregs) from periphery-induced Tregs (iTregs) (1). However, concerns have been raised and Helios expression was induced in Foxp3+ T cells (2–4). More recently, a strong Helios expression in iTregs was shown, excluding its value as a marker of nTregs (5). Without the generation of a reporter mouse for Helios, it would be impossible to determine the exact origin and function of Helios+/− Tregs (6). Regardless of this debate, there are important conclusions that can be made.
Helios in peripheral and tumor-infiltrating Foxp3+ Tregs is of particular interest. Expanded Foxp3+ Tregs in cancer patients express Helios (7). Tumor-infiltrating Foxp3+ Tregs are largely positive for Helios (Refs. 4, 8, 9 and E. Elkord, S. Sharma, D.J. Burt, and R.E. Hawkins, unpublished observations). The increased Tregs in some tumors could be derived from nTregs, but this should be interpreted carefully. Helios is a marker of T cell activation (2), and Foxp3+Helios+ Tregs do not secrete effector cytokines (10), indicating they are bona fide Tregs (11). Interestingly, Helios+ Tregs express higher levels of TGF-β, proliferate more in vivo, while the suppressive activity correlates with the absolute number of Helios+ cells (4). Therefore, Foxp3+Helios+ Tregs represent a functional subset with more suppressive characteristics, compared to Foxp3+Helios− Tregs.
Several questions need to be answered. Do higher levels of Foxp3+Helios+ Tregs correlate with poorer prognoses in cancer patients? Could Foxp3+Helios+ be the optimal subpopulation for biotherapy of autoimmune diseases? What are the main phenotypic/functional differences between Foxp3+Helios+ and Foxp3+Helios− Tregs? What is the exact role of Helios in Foxp3+/− T cells?
