iNKT cell development requires miRNA-dependent modulation of TGFβ signaling  — ASN Events
  1. Schedule
  2. Session 1 - Development and Subsets I
  3. iNKT cell development requires miRNA-dependent modulation of TGFβ signaling 

iNKT cell development requires miRNA-dependent modulation of TGFβ signaling  (#7)

Maya Fedeli 1 , Michela Riba 2 , Jose M Garcia Manteiga 2 , Lei Tian 3 , Valentina Viganò 1 , Grazisa Rossetti 4 , Massimiliano Pagani 4 , Adrian Liston 3 , Sergio Abrignani 4 , Davide Cittaro 2 , Paolo Provero 2 , Paolo Dellabona 1 , Giulia Casorati 1
  1. Division of Immunology, Transplantation and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
  2. Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy
  3. Katholieke Universiteit, Leuven, Belgium
  4. INGM-National Institute of Molecular Genetics, Milan, Italy

iNKT cells display innate effector functions that are acquired through a distinct developmental program critically regulated by microRNAs (miRNAs). To gain mechanistic insight into this program, the trascriptome of thymic iNKT cells lacking miRNAs (iNKT-Dicer-/-) was compared with that of WT cells (iNKT-WT) and searched for the enrichment of target sequences for iNKT cell-specific miRNAs in the expressed transcripts. TGFβRII, a molecule critically implicated in iNKT cell maturation, was found upregulated in iNKT-Dicer-/- cells together with an increased TGFβ-dependent signaling. miRNAs belonging to the paralogous miR-106a-363, miR-106b-25 and miR-17-92 clusters were predicted to target TGFβRII transcript during iNKT cell development. iNKT cells from mice devoid of the three miRNA clusters displayed increased TGFβRII expression and TGFβ-dependent signaling, and a maturation block that phenocopied those of iNKT-Dicer-/- cells. Finally, genetic complementation showed that iNKT cell maturation was restored by crossing Dicer-/-with TGFβRII-/- mice, supporting epistatic connections between miRNAs and TGFβ-dependent signaling. Our results, hence, highlight a fundamental requirement for the modulation of TGFβ-dependent signaling by defined miRNAs during iNKT cell development.