Bruzzaniti, Sara (2022) Glucose determines unstable FoxP3 expression and favours the development of poorly functional Treg cells in recent-onset Type 1 Diabetes children. [Tesi di dottorato]

Anteprima

Testo Bruzzaniti_Sara_35.pdf Download (5MB) | Anteprima

Abstract

Type 1 diabetes (T1D) is an autoimmune disorder caused by the destruction of insulin-producing beta-cells in the pancreas by autoreactive T cells. The disease starts years before the clinical manifestation with a progressive loss of pancreatic functions, leading to unbalanced blood glucose levels, due to low insulin production. Damage of the beta-cells is largely ascribed to unrestrained activation of effector T cells associated with defective suppressive activity of regulatory T (Treg) cells expressing the forkhead box P3 (FoxP3) transcription factor. This cell subset plays a key role in the maintenance of immune tolerance and it is now established that a reduced frequency and function of Treg cells are one of the main causes of uncontrolled autoreactive responses. While contrasting results are present about their frequency in literature, it is now clear that in autoimmune diabetes Treg cells are defective in their suppressive capability. However, the molecular mechanisms at the basis of their impaired functions are not completely elucidated. We believed that a dysregulated glucose homeostasis in T1D individuals may affect the capacity of the immune system to generate an appropriate regulatory response, thus accelerating the loss of immunological self-tolerance. For this reason, this thesis has been designed to ascertain whether glucose levels and their oscillations during T1D progression can impact a proper Treg cell generation and function, by affecting FoxP3 expression. Here, by analyzing a large cohort of T1D children at diagnosis we provided evidence indicating an increased frequency of poor functional Treg cells which is directly associated with reduced beta-cell mass and poor glycaemic control. Of note, the frequency of peripheral Treg cells decreased one year later the disease onset reflecting the differences in glucose control (measured by Continuous Glucose Monitoring). To the best of our knowledge, this thesis is the first to show that the frequency of Treg cells, measured by the expression of the transcription factor FoxP3, correlates with glycaemic levels in T1D. Further, we noticed that Tconv cells from T1D children at onset had higher glycolytic capacity than those derived from healthy children, and this event was associated with an increased ability to generate induced (i) FoxP3 Treg cells. Mechanistically, in these conditions, the enolase-1 enzyme, engaged in the glycolytic pathway, was unable to bind the regulator region of FOXP3 and repress its transcription. However, iTreg cells from T1D individuals had a reduced capability to suppress the proliferation of effector CD4+ T cells due to the transient expression of FoxP3. Strikingly, TGF-beta and IL-2 supplementation, upon iTreg cell generation, stabilized FoxP3 expression and restored Treg cell suppressive capability in T1D children at onset. Collectively, these data suggest that dysregulated glucose levels represent an accelerating factor of autoimmune reaction by favouring the generation of poorly functional Treg cells, due to unstable FoxP3 expression. Results of this thesis could open the way to identify drug interventions aiming at stabilizing FoxP3 and restoring their suppressive functions during T1D development and progression.

Downloads

Actions (login required)

Modifica documento