MicroRNA-mediated dysregulation of Th9 differentiation in islet autoimmunity

• Applicant: Dr. Isabelle Serr
• Subject Area: Immunology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 451393775

Type 1 diabetes (T1D) afflicts millions of people worldwide with rising incidence, especially in young children. Pre-symptomatic T1D (islet autoimmunity), is characterized by aberrations in immune tolerance vs. immune activation, mediated by effector T cell populations. MicroRNAs (miRs) are critical regulators of immune function and homeostasis and control complex cellular states, such as T cell activation. We have previously shown that several miRs are differentially regulated in children with vs. without islet autoimmunity. Furthermore, aberrant expression of several miRs contributes to impairments in regulatory T cell (Treg) induction, function and stability while impacting aberrant induction and activation of effector T cell populations. Th9 cells and their signature cytokine IL9 are involved in autoimmune and allergic processes, while studies suggest pleiotropic functions for IL9, including pro- and anti-inflammatory properties. Despite these insights, the molecular underpinnings guiding Th9 differentiation and the role of Th9 cells in T1D remain largely undefined. In preliminary experiments, we found miR150-5p to be reduced in CD4+T cells of children and NOD mice with islet autoimmunity, while miR150-5p is predicted to target components of the PI3K signaling pathway. Importantly, Th9 differentiation was reduced in miR150-5p deficient CD4+T cells, which could be restored by inhibiting PI3K signaling. In line with aberrant activation of PI3K signaling in NOD mice we observed a distinct reduction in Th9 differentiation in CD4+T cells from NOD mice compared to controls. These findings led us to hypothesize, that a miR150-5p/PI3K signaling axis guides Th9 differentiation in islet autoimmunity. Here, we aim to dissect the contribution of miR150-5p/PI3K signaling to Th9 differentiation with a focus on islet autoimmunity. Specifically, we will use NOD mice with islet autoimmunity and different disease courses (more vs. less aggressive) compared to non-autoimmune prone strains. Our proposed experiments will contribute to a better understanding of the regulation of Th9 cells and their role in islet autoimmunity. Therefore, the proposed studies have great potential to identify novel mechanisms relevant for future immune-based targeting of autoimmunity in order to combat the challenges imposed by T1D and its related comorbidities.

• DFG Programme: Research Grants
• Co-Investigator: Professorin Dr. Carolin Daniel