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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.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC8149963 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:RationaleInflammatory monocyte (MC) subset differentiation is a major feature in tissue inflammatory and atherosclerosis. The underlying molecular mechanism remains unclear.ObjectiveThis study aims to explore molecule targets and signaling which determinate immunological features in MC subsets.Methods and resultsBlood Ly6Chigh and Ly6Clow MC subsets from control and ApoE -/- mice were isolated by flow cytometry sorting and subjected for bulk high-throughput RNA-sequencing. Intensive bioinformatic studies were performed by analyzing transcriptome through four pairs of comparisons: A) Ly6Chigh vs Ly6Clow in control mice; B) Ly6Chigh vs Ly6Clow in ApoE-/- mice; C) ApoE-/- Ly6Chigh vs control Ly6Chigh MC; D) ApoE-/- Ly6Clow vs control Ly6Clow MC. A total of 80 canonical pathways and 16 enriched pathways were recognized by top-down analysis using IPA and GSEA software, and further used for overlapping analysis. Immunological features and signaling were assessed on four selected functional groups, including MHCII, immune checkpoint, cytokine, and transcription factor (TF). Among the total 14578 significantly differentially expressed (SDE) genes identified though above four comparison, 1051 TF and 348 immunological genes were discovered. SDE immunological genes were matched with corresponding upstream SDE TF by IPA upstream analysis. Fourteen potential transcriptional axes were recognized to modulate immunological features in the Ly6C MC subset. Based on an intensive literature search, we found that the identified SDE immune checkpoint genes in Ly6Chigh MC are associated with pro-inflammatory/atherogenic balance function. Immune checkpoint genes GITR, CTLA4, and CD96 were upregulated in Ly6Clow MC from all mice and presented anti-inflammatory/atherogenic features. Six cytokine genes, including Ccl2, Tnfsf14, Il1rn, Cxcl10, Ccl9, and Cxcl2, were upregulated in Ly6Chigh MC from all mice and associated with pro-inflammatory/atherogenic feature. Cytokine receptor gene Il12rb2, Il1r1, Il27ra, Il5ra, Ngfr, Ccr7, and Cxcr5 were upregulated in Ly6Clow MC from all mice and presented anti-inflammatory/atherogenic features. MHCII genes (H2-Oa, H2-DMb2, H2-Ob, H2-Eb2, H2-Eb1, H2-Aa, and Cd74) were elevated in Ly6Clow MC from all mice. ApoE -/- augmented pro-atherogenic/inflammatory and antigen-presenting cells (APC) feature in both subsets due to elevated expression of cytokine genes (Cxcl11, Cntf, Il24, Xcl, Ccr5, Mpl, and Acvr2a) and MHCII gene (H2-Aa and H2-Ea-ps). Finally, we modeled immunological gene expression changes and functional implications in MC differentiation and adaptive immune response for MC subsets from control and ApoE-/- mice.ConclusionsLy6Chigh MC presented pro-inflammatory/atherogenic features and lower APC potential. Ly6Clow MC displayed anti-inflammatory/atherogenic features and higher APC potential. ApoE -/- confers upon both subsets with augmented pro-atherogenic/inflammatory function and APC potential.

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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.

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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.

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OmicsDI is part of the ELIXIR infrastructure

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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.