CD69 downregulates autoimmune reactivity through active transforming growth factor-beta production in collagen-induced arthritis

• Published in: The Journal of clinical investigation 2003-09, Vol.112 (6), p.872-882
• Main Authors: Sancho, David, Gómez, Manuel, Viedma, Fernando, Esplugues, Enric, Gordón-Alonso, Mónica, García-López, María Angeles, de la Fuente, Hortensia, Martínez-A, Carlos, Lauzurica, Pilar, Sánchez-Madrid, Francisco
• Format: Article
• Language: English
• Subjects: Animals; Antigens, CD - genetics; Antigens, CD - immunology; Antigens, CD - metabolism; Antigens, Differentiation, T-Lymphocyte - genetics; Antigens, Differentiation, T-Lymphocyte - immunology; Antigens, Differentiation, T-Lymphocyte - metabolism; Arthritis, Experimental - immunology; Arthritis, Experimental - metabolism; Autoimmunity - physiology; Cytokines - genetics; Cytokines - immunology; Cytokines - metabolism; Down-Regulation; Foot - pathology; Humans; Inflammation - immunology; Joints - cytology; Joints - pathology; Lectins, C-Type; Mice; Mice, Inbred C57BL; Mice, Knockout; Spleen - cytology; Spleen - pathology; Synovial Fluid - cytology; Synovial Fluid - immunology; Transforming Growth Factor beta - immunology; Transforming Growth Factor beta - metabolism
• ISSN: 0021-9738
• DOI: 10.1172/JCI200319112

CD69 is induced after activation of leukocytes at inflammatory sites, but its physiological role during inflammation remains unknown. We explored the role of CD69 in autoimmune reactivity by analyzing a model of collagen-induced arthritis (CIA) in WT and CD69-deficient mice. CD69-/- mice showed higher incidence and severity of CIA, with exacerbated T and B cell immune responses to type II collagen. Levels of TGF-beta1 and TGF-beta2, which act as protective agents in CIA, were reduced in CD69-/- mice inflammatory foci, correlating with the increase in the proinflammatory cytokines IL-1beta and RANTES. Local injection of blocking anti-TGF-beta antibodies increased CIA severity and proinflammatory cytokine mRNA levels in CD69+/+ but not in CD69-/- mice. Moreover, in vitro engagement of CD69 induced total and active TGF-beta1 production in Concanavalin A-activated splenocyte subsets, mouse and human synovial leukocytes, and Jurkat stable transfectants of human CD69 but not in the parental CD69 negative cell line. Our results show that CD69 is a negative modulator of autoimmune reactivity and inflammation through the synthesis of TGF-beta, a cytokine that in turn downregulates the production of various proinflammatory mediators.