Plasticity deficits of Tregs remodeling toward Th1-like and Th17-like Tregs in individuals with type 1 diabetes.

Abstract

Purpose: To identify distinct Th-like regulatory T cell (Treg) subsets in the peripheral blood of individuals with type 1 diabetes (T1D) and investigate potential factors that affect Treg polarization within the context of autoimmunity.

Methods: A total of 49 T1D patients and 20 healthy controls (HCs) were enrolled in this study. Th-like Treg subsets, including Th1-like, Th2-like and Th17-like Tregs, as well as Th cell subsets in peripheral blood were assessed by flow cytometry. Single nucleotide polymorphisms in Treg-related genes were analyzed. The levels of inflammatory cytokines were measured by ELISA.

Results: We observed a decreased frequency of Th1-like Tregs in peripheral blood of T1D patients, while the proportion of total Foxp3⁺ Tregs remained unchanged. Moreover, an imbalance of Th17-like Treg/Th17 cells was noted, characterized by a decreased frequency of Th17-like Tregs and an increased proportion of Th17 cells. Further analysis revealed a correlation between the frequency of Th2-like Tregs and the risk variants of IL-2RA rs3118470. Notably, T1D patients with a normal weight exhibited a higher frequency of Th1-like Tregs compared to their lean and overweight counterparts. However, Treg plasticity was not associated with disease characteristics. Additionally, the serum levels of IL-1β, TNF-α and IL-6 in T1D patients were significantly higher than those in HCs, and the proportions of Th1-like and Th2-like Tregs were negatively associated with IL-6 and TNF-α concentrations in T1D patients, respectively. Nevertheless, the proportions of Th-like Treg subsets in the peripheral blood of HCs exhibited no significant correlation with age, BMI, or the levels of inflammatory cytokines.

Conclusion: Our study has provided novel evidence on the altered plasticity and the possible mechanisms underlying the transformation of conventional Tregs towards Th1-like and Th17-like Tregs in the peripheral blood of T1D patients. The findings serve to further augment our understanding of the Treg-mediated immune imbalance that plays a crucial role in the immunopathogenesis of T1D.