Thymus-Derived Regulatory T Cell Development Is Regulated by C-Type Lectin-Mediated BIC/MicroRNA 155 Expression.
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 withcd69-/-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 inIl2rγ-/-/cd69-/-mice. Our data highlight the contribution of CD69 as a nonredundant key regulator of BIC/miR-155-dependent Treg cell development and homeostasis.
Signaling and Inflammation Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.|CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain.
Raquel
R
Sánchez-Díaz
Signaling and Inflammation Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Rafael
R
Blanco-Dominguez
Signaling and Inflammation Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.|CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain.
Sandra
S
Lasarte
Signaling and Inflammation Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Katerina
K
Tsilingiri
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain.
Enrique
E
Martín-Gayo
Signaling and Inflammation Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.
Beatriz
B
Linillos-Pradillo
Department of Immunology, Hospital de la Princesa, Madrid, Spain.|CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain.
Hortensia
H
de la Fuente
Department of Immunology, Hospital de la Princesa, Madrid, Spain.|CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain.
Francisco
F
Sánchez-Madrid
Immunity and Cancer Laboratory, The Francis Crick Institute, London, United Kingdom.
Rinako
R
Nakagawa
Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, Madrid, Spain.
María L
ML
Toribio
Signaling and Inflammation Program, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain pmartinf@cnic.es.|CIBER de Enfermedades Cardiovasculares, Instituto de Salud Carlos III, Madrid, Spain.
Pilar
http://orcid.org/0000-0002-2392-1764
P
Martín
D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics*; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D002678:Chimera / Q000235:genetics; D037181:Lectins, C-Type / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D009924:Organ Culture Techniques; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000378:metabolism*; D000071222:Suppressor of Cytokine Signaling 1 Protein / Q000096:biosynthesis* / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000276:immunology; D013950:Thymus Gland / Q000166:cytology; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D037181:Lectins, C-Type; D035683:MicroRNAs; D034741:RNA, Small Interfering; D050799:STAT5 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000099192:CD69 Antigens; C532623:Mirn155 microRNA, mouse; C491590:Socs1 protein, mouse; C494093:Stat5a protein, mouse
C-type lectin; autoimmunity; miR-155; microRNA; regulatory T cell development