Sanchez-Diaz, RaquelBlanco-Dominguez, RafaelLasarte, SandraTsilingiri, KaterinaMartin-Gayo, EnriqueLinillos-Pradillo, Beatrizde la Fuente, HortensiaSanchez-Madrid, FranciscoNakagawa, RinakoToribio, Maria LMartin, Pilar2020-06-172020-06-172017-05Mol Cell Biol. 2017; 37(9):e00341-16http://hdl.handle.net/20.500.12105/10483Thymus-derived regulatory T (tTreg) cells are key to preventing autoimmune diseases, but the mechanisms involved in their development remain unsolved. Here, we show that the C-type lectin receptor CD69 controls tTreg cell development and peripheral Treg cell homeostasis through the regulation of BIC/microRNA 155 (miR-155) and its target, suppressor of cytokine signaling 1 (SOCS-1). Using Foxp3-mRFP/cd69+/- or Foxp3-mRFP/cd69-/- reporter mice and short hairpin RNA (shRNA)-mediated silencing and miR-155 transfection approaches, we found that CD69 deficiency impaired the signal transducer and activator of transcription 5 (STAT5) pathway in Foxp3+ cells. This results in BIC/miR-155 inhibition, increased SOCS-1 expression, and severely impaired tTreg cell development in embryos, adults, and Rag2-/- γc-/- hematopoietic chimeras reconstituted with cd69-/- stem cells. Accordingly, mirn155-/- mice have an impaired development of CD69+ tTreg cells and overexpression of the miR-155-induced CD69 pathway, suggesting that both molecules might be concomitantly activated in a positive-feedback loop. Moreover, in vitro-inducible CD25+ Treg (iTreg) cell development is inhibited in Il2rγ-/-/cd69-/- mice. Our data highlight the contribution of CD69 as a nonredundant key regulator of BIC/miR-155-dependent Treg cell development and homeostasis.engAMAnimalsAntigens, CDAntigens, Differentiation, T-LymphocyteCell DifferentiationCells, CulturedChimeraLectins, C-TypeMiceMice, Inbred C57BLMice, KnockoutMicroRNAsOrgan Culture TechniquesRNA InterferenceRNA, Small InterferingSTAT5 Transcription FactorSuppressor of Cytokine Signaling 1 ProteinT-Lymphocytes, RegulatoryThymus GlandAttribution-NonCommercial-NoDerivatives 4.0 Internacional2816760537910.1128/MCB.00341-161098-5549Molecular and cellular biologyopen access