Immunological balance between Treg and Th17 lymphocytes as a key element of type 1 diabetes progression in children

Type 1 diabetes (T1D) is autoimmune destruction of the beta cells of pancreatic islets. Due to complexity of that disease, the mechanisms leading to the tolerance breakdown are still not fully understood. Previous hypothesis of imbalance in the Th1 and Th2 cells as the main contributing factor has been recently changed towards role of other lymphocytes – regulatory (Treg) and IL-17A-producing (Th17). Our study aims to assess changes within Treg and Th17 cells in newly diagnosed T1D pediatric patients and their association with disease remission. Flow cytometry implementation allowed for Treg and Th17 analysis in studied groups and further combination with clinical and laboratory data. In addition, expression of diabetes-related genes was tested and evaluated in context of their association with studied lymphocytes. Initial results revealed that Treg and ratio Treg/Th17 are significantly higher in T1D than in healthy controls. Moreover, patients with lower HbA1c and daily insulin requirements demonstrated higher levels of Tregs. Similar tendency for insulin intake was also observed in reference to Th17 cells, together with high levels of these cells in patients demonstrating higher values for c-peptide after 2 years. In low-level Treg patients, that subset correlates with the c-peptide in the admission stage. In addition, higher levels of IL-10 were associated with its correlation with HbA1c and insulin dosage. In the context of gene expression, moderate associations were demonstrated in T1D subjects inter alia between CTLA4 and Treg or ratio Treg/Th17. Cumulatively, our data indicate a possible novel role of Treg and Th17 in mechanism of type 1 diabetes. Moreover, potential prognostic value of these populations has been shown in reference to diabetes remission. Graphical Abstract The graphical abstract represents the main conclusion of the study. Type 1 diabetic pediatric patients with higher levels of Tregs demonstrated decreased HbA1c and daily insulin requirement values. In addition, patients with increased levels of Th17 cells were shown to have significantly elevated amounts of c-peptide and reduced insulin requirement. Furthermore, remission rates assessment revealed that subjects with increased Treg or Th17 cells demonstrated partial remission more frequently compared to lower levels’ patients. Interestingly, Tregs were found to correlate positively with the CTLA4 expression – associated with excessive immune response control. Thus, possibly reducing autoinflammatory process and leading to higher insulin production, reflected by correlation with c-peptide values in our study. Moreover, Th17 cells were shown to be positively linked to RRAD expression – regulator of insulin tolerance and glucose metabolism. Considering its correlation with daily insulin dose, Th17 were found to affect reduced insulin requirement through RRAD-related mechanisms. Cumulatively, these data shed a new light on Treg and Th17 cells contribution to pathogenesis and progression of type 1 diabetes in children. [Graphical abstract was created with BioRender.com (https://biorender.com) (accessed on 31 May 2022). ]