Please use this identifier to cite or link to this item:http://hdl.handle.net/20.500.12105/10483
Thymus-Derived Regulatory T Cell Development Is Regulated by C-Type Lectin-Mediated BIC/MicroRNA 155 Expression.
Sanchez-Diaz, Raquel CNIC | Blanco-Dominguez, Rafael | Lasarte, Sandra | Tsilingiri, Katerina CNIC | Martin-Gayo, Enrique | Linillos-Pradillo, Beatriz | de la Fuente, Hortensia CNIC | Sanchez-Madrid, Francisco CNIC | Nakagawa, Rinako | Toribio, María L | Martin, Pilar CNIC
Mol Cell Biol. 2017; 37(9):e00341-16
Thymus-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.
Animals | Antigens, CD | Antigens, Differentiation, T-Lymphocyte | Cell Differentiation | Cells, Cultured | Chimera | Lectins, C-Type | Mice | Mice, Inbred C57BL | Mice, Knockout | MicroRNAs | Organ Culture Techniques | RNA Interference | RNA, Small Interfering | STAT5 Transcription Factor | Suppressor of Cytokine Signaling 1 Protein | T-Lymphocytes, Regulatory | Thymus Gland