Rosanio, Francesco Maria (2024) Effetti del controllo gluco-metabolico sul fenotipo, frequenza e funzione delle cellule TR3-56 nei bambini con diabete di tipo 1. [Tesi di dottorato]

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Abstract

Background. Type 1 diabetes (T1D) is an autoimmune condition marked by the progressive destruction of insulin-producing pancreatic β-cells. T cells play a central role in this process, particularly by mediating immune attacks on β-cells. Emerging evidence highlights the impact of glucose metabolism on immune cell function, suggesting that chronic hyperglycemia may exacerbate β-cell damage in T1D. Previous research from our group identified a distinct subset of T cells, named TR3-56 cells, that show altered phenotypes and functions in newly diagnosed T1D patients, raising questions about their potential role in ongoing disease progression. Aims. This study aims to examine the dynamics of TR3-56 cells one year after T1D diagnosis, focusing on changes in their frequency, function, and phenotype. Specifically, we investigated their relationship with glycemic control, as measured by continuous glucose monitoring (CGM) metrics, and investigate whether TR3-56 cells contribute to β-cell destruction in cases of poor metabolic control. Materials and Methods. We conducted a longitudinal study involving 106 children with T1D, followed for one year after diagnosis, and compared to 36 healthy controls. Blood samples were collected at diagnosis and after one year to evaluate TR3-56 cell frequency and functionality. The cohort was stratified based on glycemic control using CGM data. Flow cytometry was employed to assess cytotoxic and regulatory markers, including CD107a, IFN-γ, and Granzyme B. The cytotoxic potential of TR3-56 cells was measured in co-culture assays with CD8+ T cells. Statistical analysis explored correlations between TR3-56 cell frequencies and gluco-metabolic control, assessed by glycosylated hemoglobin (HbA1c), time in range (TIR), and time above range (TAR). Results. After one year, subjects treated with continuous subcutaneous insulin infusion (CSII) displayed better gluco-metabolic control compared to those on multiple daily injections (MDI). Regarding TR3-56 cells, their frequency was initially reduced in T1D individuals at diagnosis but partially recovered one year later. Importantly, a positive correlation emerged between TR3-56 cell frequency and markers of poor glycemic control, such as elevated HbA1c and increased TAR. Subjects with suboptimal glycemic control (TIR < 70%) exhibited higher frequencies of TR3-56 cells, enhanced cytotoxic Immunoglobulin-like receptors, including elevated expression of CD107a, Granzyme B, and IFN-γ. In contrast, the expression of inhibitory markers like NKG2A was reduced. Children treated with MDI had higher TR3-56 cell frequencies and poorer glucose control than those receiving CSII, although these were not statistically significant. Notably, TR3-56 cells in children with worse glycemic control showed a greater cytotoxic potential, although some differences, such as increased CD107a expression, did not reach statistical significance. Discussion. This study reveals a significant relationship between TR3-56 cells and glycemic control after one year after T1D diagnosis. TR3-56 cells, which initially appeared to have a regulatory function, shifted towards a cytotoxic phenotype over time, particularly in patients with poor gluco-metabolic control (TIR < 70%). These findings suggest that persistent hyperglycemia may drive this subset of T cells towards a more destructive role, contributing to continued β-cell loss. Additionally, the higher TIR in CSII-treated subjects, along with their lower TR3-56 cell frequencies, indicate that optimal glucose regulation may reduce the cytotoxic potential of these cells. Conclusion. Poor glycemic control in T1D is associated with increased frequency and cytotoxic activity of TR3-56 cells. These cells appear to be involved in β-cell destruction during T1D progression. Further functional studies are needed to understand the role of TR3-56 cells in T1D progression, and the impact of gluco-metabolic control on their frequency and functional activity, in order to better tailor new therapies aimed at preventing and slowing the progression of T1D.

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