Low-dose IL-2 therapy — a complex scenario that remains to be further explored

We thank Zhanguo Li, Jing He, and Di Yu for their correspondence (The rise of IL-2 therapy — a picture beyond T_reg cells. Nat. Rev. Rheumatol.; 2017)¹ about our commentary (Humrich, J. Y. & Riemekasten & G. The rise of IL-2 therapy — a novel biologic treatment for SLE. Nat. Rev. Rheumatol. 12, 695–696; 2016)², which discussed their study of low-dose IL-2 therapy in systemic lupus erythematosus (SLE)³.

We agree that low-dose IL-2 therapy exerts effects on other cell subsets apart from regulatory T (T_reg) cells and that the clinical efficacy of this treatment modality might not only be explained by the exclusive targeting of T_reg cells. Owing to its pleiotropy in general, IL-2, even when applied in low doses, indeed has some effects on other cells such as conventional CD4⁺ T cells, natural killer cells and CD8⁺ T cells (see also von Spee-Mayer et al.⁴).

He et al.³ focused their investigations on effects of low-dose IL-2 therapy on T follicular helper (T_FH) and type 17 T helper (T_H17) cells, which of course is a sound rationale in light of their previous observations. In their study, He et al. defined T_reg cells based on protocols reported in 2006 (Refs 5,6). However, the appropriate application of these well-elaborated protocols depends on the research questions being explored, as these protocols were mainly developed to selectively enrich human T_reg cells for in vitro functional studies. The respective studies demonstrated that the inclusion of surface CD127 for T_reg cell analysis results in an improved flow-cytometry-based distinction between genuine T_reg cells and activated conventional T cells, which transiently express CD25 in particular, as well as FOXP3 (Refs 5,6). These analyses also included staining for FOXP3 and the authors did not suggest omitting FOXP3 in flow-cytometry-based T_reg cell analyses. One of the main messages of these works was that CD127, or the combination of CD127 and CD25, is better than CD25 alone for distinguishing between T_reg cells and activated conventional T cells, which is highly relevant for the 'live' isolation of T_reg cells for functional analyses and in vitro studies^5,6.

In our previous analyses⁴, a small proportion of FOXP3⁺CD127^loCD25⁻ T cells produced cytokines (∼10–15% in patients with SLE) and we found that this cell subset was less demethylated in the T_reg-specific demethylated region compared with the FOXP3⁺CD127^loCD25⁺ T_reg cell subset, indicating that some of these FOXP3⁺CD127^loCD25⁻ T cells are indeed activated conventional T cells. However, and in contrast to cells from healthy individuals, the majority of these FOXP3⁺CD127^loCD25⁻ cells could still be considered bona fide T_reg cells in patients with SLE as they expressed high levels of surrogate markers for T_reg cells (such as Helios) and most did not express cytokines. In addition, these FOXP3⁺CD127^loCD25⁻ cells could re-express the IL-2 receptor α-chain CD25 upon IL-2 exposure⁴.

In any case, we thank our colleagues for their important contribution to this vibrant research field and we hope very much for our patients that this novel therapeutic concept will find its way into routine clinical practice regardless of its underlying mechanisms.