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

Front Immunol. 2021 May 12;12:628504. doi: 10.3389/fimmu.2021.628504. eCollection 2021.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Autoantibodies / blood*
  • Autoimmunity*
  • Biomarkers / blood
  • CTLA-4 Antigen / blood
  • Case-Control Studies
  • Diabetes Mellitus, Type 1 / blood
  • Diabetes Mellitus, Type 1 / diagnosis
  • Diabetes Mellitus, Type 1 / immunology*
  • Flow Cytometry
  • Forkhead Transcription Factors / blood
  • Humans
  • Ikaros Transcription Factor / blood*
  • Immunophenotyping
  • Interleukin-2 Receptor alpha Subunit / blood
  • Monocytes / immunology*
  • Monocytes / metabolism
  • Phenotype
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism


  • Autoantibodies
  • Biomarkers
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • IKZF2 protein, human
  • IL2RA protein, human
  • Interleukin-2 Receptor alpha Subunit
  • Ikaros Transcription Factor