miRNA92a targets KLF2 and the phosphatase PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity.

2.50
Hdl Handle:
http://hdl.handle.net/10033/621272
Title:
miRNA92a targets KLF2 and the phosphatase PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity.
Authors:
Serr, Isabelle; Fürst, Rainer W; Ott, Verena B; Scherm, Martin G; Nikolaev, Alexei; Gökmen, Füsun; Kälin, Stefanie; Zillmer, Stephanie; Bunk, Melanie; Weigmann, Benno; Kunschke, Nicole; Loretz, Brigitta; Lehr, Claus Michael ( 0000-0002-5864-8462 ) ; Kirchner, Benedikt; Haase, Bettina; Pfaffl, Michael; Waisman, Ari; Willis, Richard A; Ziegler, Anette-G; Daniel, Carolin
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.
Affiliation:
Helmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.
Citation:
miRNA92a targets KLF2 and the phosphatase PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity. 2016, 113 (43):E6659-E6668 Proc. Natl. Acad. Sci. U.S.A.
Journal:
Proceedings of the National Academy of Sciences of the United States of America
Issue Date:
2016
URI:
http://hdl.handle.net/10033/621272
DOI:
10.1073/pnas.1606646113
PubMed ID:
27791035
PubMed Central ID:
PMC5087025
Additional Links:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087025/
Type:
Article
Language:
en
ISSN:
1091-6490
Appears in Collections:
publications of the department drug delivery ([TC] DDEL)

Full metadata record

DC FieldValue Language
dc.contributor.authorSerr, Isabelleen
dc.contributor.authorFürst, Rainer Wen
dc.contributor.authorOtt, Verena Ben
dc.contributor.authorScherm, Martin Gen
dc.contributor.authorNikolaev, Alexeien
dc.contributor.authorGökmen, Füsunen
dc.contributor.authorKälin, Stefanieen
dc.contributor.authorZillmer, Stephanieen
dc.contributor.authorBunk, Melanieen
dc.contributor.authorWeigmann, Bennoen
dc.contributor.authorKunschke, Nicoleen
dc.contributor.authorLoretz, Brigittaen
dc.contributor.authorLehr, Claus Michaelen
dc.contributor.authorKirchner, Benedikten
dc.contributor.authorHaase, Bettinaen
dc.contributor.authorPfaffl, Michaelen
dc.contributor.authorWaisman, Arien
dc.contributor.authorWillis, Richard Aen
dc.contributor.authorZiegler, Anette-Gen
dc.contributor.authorDaniel, Carolinen
dc.date.accessioned2018-02-09T09:40:33Z-
dc.date.available2018-02-09T09:40:33Z-
dc.date.issued2016-
dc.identifier.citationmiRNA92a targets KLF2 and the phosphatase PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity. 2016, 113 (43):E6659-E6668 Proc. Natl. Acad. Sci. U.S.A.en
dc.identifier.issn1091-6490-
dc.identifier.pmid27791035-
dc.identifier.doi10.1073/pnas.1606646113-
dc.identifier.urihttp://hdl.handle.net/10033/621272-
dc.description.abstractAberrant 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.en
dc.language.isoenen
dc.relation.urlhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087025/en
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAdolescenten
dc.subject.meshAnimalsen
dc.subject.meshAntagomirsen
dc.subject.meshAutoantibodiesen
dc.subject.meshAutoimmunityen
dc.subject.meshChilden
dc.subject.meshDiabetes Mellitus, Type 1en
dc.subject.meshFemaleen
dc.subject.meshForkhead Box Protein O1en
dc.subject.meshGene Expression Regulationen
dc.subject.meshHumansen
dc.subject.meshIslets of Langerhansen
dc.subject.meshKruppel-Like Transcription Factorsen
dc.subject.meshMaleen
dc.subject.meshMiceen
dc.subject.meshMice, Inbred NODen
dc.subject.meshMice, Transgenicen
dc.subject.meshMicroRNAsen
dc.subject.meshPTEN Phosphohydrolaseen
dc.subject.meshPhosphatidylinositol 3-Kinasesen
dc.subject.meshPrimary Cell Cultureen
dc.subject.meshReceptors, CXCR5en
dc.subject.meshSignal Transductionen
dc.subject.meshT-Lymphocytes, Helper-Induceren
dc.titlemiRNA92a targets KLF2 and the phosphatase PTEN signaling to promote human T follicular helper precursors in T1D islet autoimmunity.en
dc.typeArticleen
dc.contributor.departmentHelmholtz-Institut für pharmazeutische Forschung Saarland, Universitätscampus E8.1, 66123 Saarbrücken, Germany.en
dc.identifier.journalProceedings of the National Academy of Sciences of the United States of Americaen
dc.identifier.pmcidPMC5087025-

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