Differences in Maturation Status and Immune Phenotypes of Circulating Helios+ and Helios- Tregs and Their Disrupted Correlations With Monocyte Subsets in Autoantibody-Positive T1D Individuals

Abstract

CD4 Tregs are involved in the regulation of various autoimmune diseases but believed to be highly heterogeneous. Studies have indicated that Helios controls a distinct subset of functional Tregs. However, the immunological changes in circulating Helios⁺ and Helios^- Tregs are not fully explored in type 1 diabetes (T1D). Here, we elucidated the differences in maturation status and immune regulatory phenotypes of Helios⁺ and Helios^- Tregs and their correlations with monocyte subsets in T1D individuals. As CD25^-/low FOXP3⁺ Tregs also represent a subset of functional Tregs, we defined Tregs as FOXP3⁺CD127^-/low and examined circulating Helios⁺ and Helios^- Treg subpopulations in 68 autoantibody-positive T1D individuals and 68 age-matched healthy controls. We found that expression of both FOXP3 and CTLA4 diminished in Helios^- Tregs, while the proportion of CD25^-/low Tregs increased in Helios⁺ Tregs of T1D individuals. Although the frequencies of neither Helios⁺ nor Helios^- Tregs were affected by investigated T1D genetic risk loci, Helios⁺ Tregs correlated with age at T1D diagnosis negatively and disease duration positively. Moreover, the negative correlation between central and effector memory proportions of Helios⁺ Tregs in healthy controls was disrupted in T1D individuals. Finally, regulatory non-classical and intermediate monocytes also decreased in T1D individuals, and positive correlations between these regulatory monocytes and Helios⁺/Helios^- Treg subsets in healthy controls disappeared in T1D individuals. In conclusion, we demonstrated the alternations in maturation status and immune phenotypes in Helios⁺ and Helios^- Treg subsets and revealed the missing association between these Treg subsets and monocyte subsets in T1D individuals, which might point out another option for elucidating T1D mechanisms.

Keywords: Helios; Tregs; monocytes; regulatory; type 1 diabetes.