miR-181a/b-1 controls thymic selection of Treg cells and tunes their suppressive capacity

by Marcin Łyszkiewicz, Samantha J. Winter, Katrin Witzlau, Lisa Föhse, Rebecca Brownlie, Jacek Puchałka, Nikita A. Verheyden, Heike Kunze-Schumacher, Esther Imelmann, Jonas Blume, Solaiman Raha, Takashi Sekiya, Akihiko Yoshimura, Jochen T. Frueh, Evelyn Ullrich, Jochen Huehn, Siegfried Weiss, Maximiliano G. Gutierrez, Immo Prinz, Rose Zamoyska, Natalia Ziętara, Andreas Krueger

The interdependence of selective cues during development of regulatory T cells (Treg cells) in the thymus and their suppressive function remains incompletely understood. Here, we analyzed this interdependence by taking advantage of highly dynamic changes in expression of microRNA 181 family members miR-181a-1 and miR-181b-1 (miR-181a/b-1) during late T-cell development with very high levels of expression during thymocyte selection, followed by massive down-regulation in the periphery. Loss of miR-181a/b-1 resulted in inefficient de novo generation of Treg cells in the thymus but simultaneously permitted homeostatic expansion in the periphery in the absence of competition. Modulation of T-cell receptor (TCR) signal strength in vivo indicated that miR-181a/b-1 controlled Treg-cell formation via establishing adequate signaling thresholds. Unexpectedly, miR-181a/b-1–deficient Treg cells displayed elevated suppressive capacity in vivo, in line with elevated levels of cytotoxic T-lymphocyte–associated 4 (CTLA-4) protein, but not mRNA, in thymic and peripheral Treg cells. Therefore, we propose that intrathymic miR-181a/b-1 controls development of Treg cells and imposes a developmental legacy on their peripheral function.