title: miRNA92a targets KLF2 and the phosphatase PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity.
abstract: Aberrant immune activation mediated by T effector cell populations is pivotal in the onset of autoimmunity in type 1 diabetes (T1D). T follicular helper (TFH) cells are essential in the induction of high-affinity antibodies, and their precursor memory compartment circulates in the blood. The role of TFH precursors in the onset of islet autoimmunity and signaling pathways regulating their differentiation is incompletely understood. Here, we provide direct evidence that during onset of islet autoimmunity, the insulin-specific target T-cell population is enriched with a C-X-C chemokine receptor type 5 (CXCR5)+CD4+TFH precursor phenotype. During onset of islet autoimmunity, the frequency of TFH precursors was controlled by high expression of microRNA92a (miRNA92a). miRNA92a-mediated TFH precursor induction was regulated by phosphatase and tension homolog (PTEN) - phosphoinositol-3-kinase (PI3K) signaling involving PTEN and forkhead box protein O1 (Foxo1), supporting autoantibody generation and triggering the onset of islet autoimmunity. Moreover, we identify Krueppel-like factor 2 (KLF2) as a target of miRNA92a in regulating human TFH precursor induction. Importantly, a miRNA92a antagomir completely blocked induction of human TFH precursors in vitro. More importantly, in vivo application of a miRNA92a antagomir to nonobese diabetic (NOD) mice with ongoing islet autoimmunity resulted in a significant reduction of TFH precursors in peripheral blood and pancreatic lymph nodes. Moreover, miRNA92a antagomir application reduced immune infiltration and activation in pancreata of NOD mice as well as humanized NOD Scid IL2 receptor gamma chain knockout (NSG) human leucocyte antigen (HLA)-DQ8 transgenic animals. We therefore propose that miRNA92a and the PTEN-PI3K-KLF2 signaling network could function as targets for innovative precision medicines to reduce T1D islet autoimmunity.
authors: Institute for Diabetes Research, Independent Young Investigator Group Immune Tolerance in Type 1 Diabetes, Helmholtz Diabetes Center at Helmholtz Zentrum München, 80939 Munich, Germany; Deutsches Zentrum für Diabetesforschung, 85764 Munich, Germany.
authors: Isabelle
authors: I
authors: Serr
authors: Deutsches Zentrum für Diabetesforschung, 85764 Munich, Germany; Institute for Diabetes Research, Helmholtz Diabetes Center at Helmholtz Zentrum München, 80939 Munich, Germany; Klinikum rechts der Isar, Technische Universität München, 80939 Munich, Germany.
authors: Rainer W
authors: RW
authors: Fürst
authors: Deutsches Zentrum für Diabetesforschung, 85764 Munich, Germany; Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, 80939 Munich, Germany; Division of Metabolic Diseases, Technische Universität München, 85748 Munich, Germany.
authors: Verena B
authors: VB
authors: Ott
authors: Institute for Diabetes Research, Independent Young Investigator Group Immune Tolerance in Type 1 Diabetes, Helmholtz Diabetes Center at Helmholtz Zentrum München, 80939 Munich, Germany; Deutsches Zentrum für Diabetesforschung, 85764 Munich, Germany.
authors: Martin G
authors: MG
authors: Scherm
authors: Institute for Molecular Medicine, Universitätsmedizin der Johannes Gutenberg-Universität, 55131 Mainz, Germany.
authors: Alexei
authors: A
authors: Nikolaev
authors: Institute for Diabetes Research, Independent Young Investigator Group Immune Tolerance in Type 1 Diabetes, Helmholtz Diabetes Center at Helmholtz Zentrum München, 80939 Munich, Germany; Deutsches Zentrum für Diabetesforschung, 85764 Munich, Germany.
authors: Füsun
authors: F
authors: Gökmen
authors: Deutsches Zentrum für Diabetesforschung, 85764 Munich, Germany; Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, 80939 Munich, Germany; Division of Metabolic Diseases, Technische Universität München, 85748 Munich, Germany.
authors: Stefanie
authors: S
authors: Kälin
authors: Deutsches Zentrum für Diabetesforschung, 85764 Munich, Germany; Institute for Diabetes Research, Helmholtz Diabetes Center at Helmholtz Zentrum München, 80939 Munich, Germany; Klinikum rechts der Isar, Technische Universität München, 80939 Munich, Germany.
authors: Stephanie
authors: S
authors: Zillmer
authors: Deutsches Zentrum für Diabetesforschung, 85764 Munich, Germany; Institute for Diabetes Research, Helmholtz Diabetes Center at Helmholtz Zentrum München, 80939 Munich, Germany; Klinikum rechts der Isar, Technische Universität München, 80939 Munich, Germany.
authors: Melanie
authors: M
authors: Bunk
authors: Department of Medicine 1, University of Erlangen-Nuremberg, Kussmaul Campus for Medical Research, 91052 Erlangen, Germany.
authors: Benno
authors: B
authors: Weigmann
authors: Department of Drug Delivery, Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research, 66123 Saarbruecken, Germany.
authors: Nicole
authors: N
authors: Kunschke
authors: Department of Drug Delivery, Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research, 66123 Saarbruecken, Germany.
authors: Brigitta
authors: B
authors: Loretz
authors: Department of Drug Delivery, Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research, 66123 Saarbruecken, Germany; Department of Pharmacy, Saarland University, 66123 Saarbruecken, Germany.
authors: Claus-Michael
authors: 0000-0002-5864-8462
authors: CM
authors: Lehr
authors: Physiology Weihenstephan, Technische Universität München, 85354 Freising, Germany.
authors: Benedikt
authors: B
authors: Kirchner
authors: Genomics Core Facility, European Molecular Biology Laboratory, 69117 Heidelberg, Germany.
authors: Bettina
authors: B
authors: Haase
authors: Physiology Weihenstephan, Technische Universität München, 85354 Freising, Germany.
authors: Michael
authors: M
authors: Pfaffl
authors: Institute for Molecular Medicine, Universitätsmedizin der Johannes Gutenberg-Universität, 55131 Mainz, Germany.
authors: Ari
authors: A
authors: Waisman
authors: Emory Vaccine Center, NIH Tetramer Core Facility, Atlanta, GA 30322.
authors: Richard A
authors: RA
authors: Willis
authors: Deutsches Zentrum für Diabetesforschung, 85764 Munich, Germany; Institute for Diabetes Research, Helmholtz Diabetes Center at Helmholtz Zentrum München, 80939 Munich, Germany; Klinikum rechts der Isar, Technische Universität München, 80939 Munich, Germany.
authors: Anette-G
authors: AG
authors: Ziegler
authors: Institute for Diabetes Research, Independent Young Investigator Group Immune Tolerance in Type 1 Diabetes, Helmholtz Diabetes Center at Helmholtz Zentrum München, 80939 Munich, Germany; Deutsches Zentrum für Diabetesforschung, 85764 Munich, Germany; carolin.daniel@helmholtz-muenchen.de.
authors: Carolin
authors: C
authors: Daniel
mesh_terms: D000293:Adolescent; D000818:Animals; D000070416:Antagomirs / Q000235:genetics / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis; D015551:Autoimmunity; D002648:Child; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D000071161:Forkhead Box Protein O1 / Q000235:genetics / Q000276:immunology; D005786:Gene Expression Regulation; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000276:immunology*; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000276:immunology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology; D061251:Primary Cell Culture; D054380:Receptors, CXCR5 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000473:pathology
chemical_list: D000070416:Antagomirs; D001323:Autoantibodies; C095085:CXCR5 protein, human; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D054380:Receptors, CXCR5; D019869:Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: KLF2; PTEN-PI3K signaling; T follicular helper cells; miRNA92a; type 1 diabetes