10779/crick.11378580.v1 Marcin Łyszkiewicz Marcin Łyszkiewicz Samantha J Winter Samantha J Winter Katrin Witzlau Katrin Witzlau Lisa Föhse Lisa Föhse Rebecca Brownlie Rebecca Brownlie Jacek Puchałka Jacek Puchałka Nikita A Verheyden Nikita A Verheyden Heike Kunze-Schumacher Heike Kunze-Schumacher Esther Imelmann Esther Imelmann Jonas Blume Jonas Blume Solaiman Raha Solaiman Raha Takashi Sekiya Takashi Sekiya Akihiko Yoshimura Akihiko Yoshimura Jochen T Frueh Jochen T Frueh Evelyn Ullrich Evelyn Ullrich Jochen Huehn Jochen Huehn Siegfried Weiss Siegfried Weiss Maximiliano G Gutierrez Maximiliano G Gutierrez Immo Prinz Immo Prinz Rose Zamoyska Rose Zamoyska Natalia Ziętara Natalia Ziętara Andreas Krueger Andreas Krueger miR-181a/b-1 controls thymic selection of Treg cells and tunes their suppressive capacity The Francis Crick Institute 2019 Animals Flow Cytometry Mice Mice, Knockout MicroRNAs Microscopy, Confocal Nuclear Receptor Subfamily 4, Group A, Member 1 Nuclear Receptor Subfamily 4, Group A, Member 2 T-Lymphocytes, Regulatory Thymocytes Gutierrez FC001092 Developmental Biology 06 Biological Sciences 11 Medical and Health Sciences 07 Agricultural and Veterinary Sciences 2019-12-17 16:37:21 Journal contribution https://crick.figshare.com/articles/journal_contribution/miR-181a_b-1_controls_thymic_selection_of_Treg_cells_and_tunes_their_suppressive_capacity/11378580 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.