title: Maintenance of immune tolerance by Foxp3+ regulatory T cells requires CD69 expression.
abstract: Although FoxP3(+) regulatory T cells are key players in the maintenance of immune tolerance and autoimmunity, the lack of specific markers constitute an obstacle to their use for immunotherapy protocols. In this study, we have investigated the role of the C-type lectin receptor CD69 in the suppressor function of Tregs and maintenance of immune tolerance towards harmless inhaled antigens. We identified a novel FoxP3(+)CD69(+) Treg subset capable to maintain immune tolerance and protect to developing inflammation. Although CD69(+) and CD69(-)FoxP3(+) Tregs exist in homeostasis, only CD69-expressing Tregs express high levels of CTLA-4, ICOS, CD38 and GITR suppression-associated markers, secrete high amounts of TGFβ and have potent suppressor activity. This activity is regulated by STAT5 and ERK signaling pathways and is impaired by antibody-mediated down-regulation of CD69 expression. Moreover, immunotherapy with FoxP3(+)CD69(+) Tregs restores the homeostasis in Cd69(-/-) mice, that fail to induce tolerance, and is also highly proficient in the prevention of inflammation. The identification of the FoxP3(+)CD69(+) Treg subset paves the way toward the development of new therapeutic strategies to control immune homeostasis and autoimmunity.
authors.affiliation: Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, 28029 Spain.
authors.forename: José R
authors.initials: JR
authors.lastname: Cortés
authors.affiliation: Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, 28029 Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Sánchez-Díaz
authors.affiliation: Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, 28029 Spain.
authors.forename: Elena R
authors.initials: ER
authors.lastname: Bovolenta
authors.affiliation: Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, 28029 Spain.
authors.forename: Olga
authors.initials: O
authors.lastname: Barreiro
authors.affiliation: Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, 28029 Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Lasarte
authors.affiliation: Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, 28029 Spain.
authors.forename: Adela
authors.initials: A
authors.lastname: Matesanz-Marín
authors.affiliation: Centro de Biología Molecular Severo Ochoa, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, 28049 Spain.
authors.forename: María L
authors.initials: ML
authors.lastname: Toribio
authors.affiliation: Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, 28029 Spain.|Servicio de Inmunología, Hospital de La Princesa, Universidad Autónoma de Madrid, Madrid, 28006 Spain.
authors.forename: Francisco
authors.initials: F
authors.lastname: Sánchez-Madrid
authors.affiliation: Department of Vascular Biology and Inflammation, Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, 28029 Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Martín
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology*; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology*; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance / Q000502:physiology*; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D037181:Lectins, C-Type; D016212:Transforming Growth Factor beta; D000099192:CD69 Antigens
keywords: CD69; FoxP3; Immune tolerance; Regulatory T cells