MicroRNA-vermittelte Dysregulation der Th9 Differenzierung in Inselautoimmunität

• Antragstellerin: Dr. Isabelle Serr
• Fachliche Zuordnung: Immunologie
• Förderung: Förderung von 2021 bis 2024
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 451393775

• Erstellungsjahr: 2024

Zusammenfassung der Projektergebnisse

Type 1 diabetes (T1D) has been linked to critical Treg impairments, however, the mechanisms and cellular contributors are still insufficiently understood. In NOD mice overshooting PI3K-Akt signaling was shown to reduce Treg induction, function and stability. PI3K-Akt signaling also regulates Th9 cell induction, a CD4+T cell subtype that secretes Il9, a cytokine with context-dependent pro- or anti-inflammatory properties. However, the role of Th9 cells and Il9 has not been studied in T1D before. Strikingly, in vitro Th9 induction is strongly impaired in NOD vs. non-autoimmune-prone Balbc mice, which can be partly restored by AKT inhibition. Among the possible molecular factors involved in this impairment, microRNAs (miRs) come into play, being regulators of complex cellular states. From RNA sequencing experiments, one candidate miR possibly involved in the regulation of the pathway, is miR150-5p, which we found to be downregulated in children and mice with islet autoimmunity. miR target prediction and HITS-CLIP analysis indicate that miR150-5p targets components of PI3K-AKT signalling, and specifically Akt3, which we confirmed as a direct target in luciferase assays. Interestingly, siRNA-mediated silencing of Akt3 or the delivery of a miR150-5p mimic, improves in vitro Th9 induction in NOD mice. Il9 can excert anti-inflmmatory functions by fostering Tregs. Accordingly, we demonstrate a reduction in in vitro Treg induction, effector Treg frequencies in the pancreas and Treg suppression in vitro in Il9 deficient mice. Importantly, the treatment of NOD mice with recombinant Il9 in vivo resulted in signifcantly increased frequencies of insulin-specific Tregs in the pancreas and reduced insulits scores. Overall, our data highlight Th9 cells and the miR150-5p-AKT3 signaling pathway as potential novel targets for immune intervention to foster Tregs in T1D.

Projektbezogene Publikationen (Auswahl)

• Th9 cells – novel players in the regulation of islet autoimmunity. In: Deutsches Zentrum für Diabetesforschung (DZD) Workshop; 2022 May 2; online
  Serr I.
  
• Early onset Treg impairments in islet autoimmunity. In: SFB1054 annual meeting; 2023 Oct 24; San Servolo, Italy
  Serr I.
  
• miRNA150 targets Akt3 signaling to shape Th9 differentiation in models of type 1 diabetes. In: Immunology of Diabetes Society (IDS) Congress; 2023 May 23- 27; Paris, France
  Serr I., Boschi G., Scherm M.G., Weigmann B. & Daniel C.
  
• Th9 cells – novel regulators of islet autoimmunity. In: 6th Helmholtz Immunology Workshop; 2023 Oct 18; online
  Serr I.
  
• miRNA150 targets Akt3 signaling to shape Th9 differentiation in models of type 1 diabetes. In: Harald von Boehmer Midwinter Conference (MWC) Advances in Immunobiology; 2024 Jan 20-24; Seefeld, Austria
  Serr I., Surnov A. & Daniel C.
  
• miRNA150 targets Akt3 signaling to shape Th9 differentiation in models of type 1 diabetes. In: Immunology of Diabetes Society (IDS) Congress; 2024 Nov 4- 8; Bruge, Belgium
  Bührer A-M., Serr I., Surnov A. & Daniel C.
  
• Opportunities for Immunotherapies in Type 1 Diabetes. In: Helmholtz Research School for Diabetes (HRD) Introduction to Diabetes Research; 2024 Jan 26; Neuherberg, Germany
  Serr I.
  
• Th9 cells – novel players in islet autoimmunity. In: Deutsches Zentrum für Diabetesforschung (DZD) Joint Meeting of the T1D and Beta Cell Academies; 2024 Nov 14; online
  Serr I.