Overexpression of V alpha 14J alpha 18 TCR promotes development of iNKT cells in the absence of miR-181a/b-1

Blume, Jonas; Zur Lage, Susanne; Witzlau, Katrin; Georgiev, Hristo; Weiss, Siegfried; Łyszkiewicz, Marcin; Ziętara, Natalia und Krueger, Andreas (2016): Overexpression of V alpha 14J alpha 18 TCR promotes development of iNKT cells in the absence of miR-181a/b-1. In: Immunology and Cell Biology, Bd. 94, Nr. 8: S. 741-746

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 V alpha 14J alpha 18 TCR alpha chain. In these mice, development of iNKT cells was fully restored. Furthermore, both subset distribution of iNKT cells as well as TCR V beta repertoire were independent of the presence of miR-181a/b-1 once a V alpha 14J alpha 18 TCR alpha chain was overexpressed. Finally, levels of Pten protein were similar in V alpha 14J alpha 18 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0818-9641
• Sprache: Englisch