title: Overexpression of Vα14Jα18 TCR promotes development of iNKT cells in the absence of miR-181a/b-1.
abstract: Expression of microRNA miR-181a/b-1 is critical for intrathymic development of invariant natural killer T (iNKT) cells. However, the underlying mechanism has remained a matter of debate. On the one hand, growing evidence suggested that miR-181a/b-1 is instrumental in setting T-cell receptor (TCR) signaling threshold and thus permits agonist selection of iNKT cells through high-affinity TCR ligands. On the other hand, alterations in metabolic fitness mediated by miR-181a/b-1-dependent dysregulation of phosphatase and tensin homolog (Pten) have been proposed to cause the iNKT-cell defect in miR-181-a/b-1-deficient mice. To re-assess the hypothesis that modulation of TCR signal strength is the key mechanism by which miR-181a/b-1 controls the development of iNKT cells, we generated miR-181a/b-1-deficient mice expressing elevated levels of a Vα14Jα18 TCRα chain. In these mice, development of iNKT cells was fully restored. Furthermore, both subset distribution of iNKT cells as well as TCR Vβ repertoire were independent of the presence of miR-181a/b-1 once a Vα14Jα18 TCRα chain was overexpressed. Finally, levels of Pten protein were similar in Vα14Jα18 transgenic mice irrespective of their miR-181a/b-1 status. Collectively, our data support a model in which miR-181 promotes development of iNKT cells primarily by generating a permissive state for agonist selection with alterations in metabolic fitness possibly constituting a secondary effect.
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Jonas
authors.initials: J
authors.lastname: Blume
authors.affiliation: Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Zur Lage
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Witzlau
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Hristo
authors.initials: H
authors.lastname: Georgiev
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.|Molecular Immunology, Helmholtz Centre for Infection Research, Braunschweig, Germany.
authors.forename: Siegfried
authors.initials: S
authors.lastname: Weiss
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Marcin
authors.initials: M
authors.lastname: Łyszkiewicz
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Natalia
authors.initials: N
authors.lastname: Ziȩtara
authors.affiliation: Institute of Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Krueger
mesh_terms: D000818:Animals; D016764:Cell Polarity; D016131:Lymphocyte Subsets / Q000276:immunology; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D055611:Natural Killer T-Cells / Q000166:cytology* / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism*; D019076:Transgenes
chemical_list: D035683:MicroRNAs; D016693:Receptors, Antigen, T-Cell, alpha-beta; C529100:mirn181 microRNA, mouse; D051059:PTEN Phosphohydrolase