CD69 downregulates autoimmune reactivity through active transforming growth factor-β production in collagen-induced arthritis
David Sancho, Manuel Gómez, Fernando Viedma, Enric Esplugues, Mónica Gordón-Alonso, María Angeles García-López, Hortensia de la Fuente, Carlos Martínez-A, Pilar Lauzurica, Francisco Sánchez-Madrid
David Sancho, Manuel Gómez, Fernando Viedma, Enric Esplugues, Mónica Gordón-Alonso, María Angeles García-López, Hortensia de la Fuente, Carlos Martínez-A, Pilar Lauzurica, Francisco Sánchez-Madrid
View: Text | PDF
Article Immunology

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

Abstract

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-β1 and TGF-β2, which act as protective agents in CIA, were reduced in CD69–/– mice inflammatory foci, correlating with the increase in the proinflammatory cytokines IL-1β and RANTES. Local injection of blocking anti–TGF-β 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-β1 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-β, a cytokine that in turn downregulates the production of various proinflammatory mediators.

Authors

David Sancho, Manuel Gómez, Fernando Viedma, Enric Esplugues, Mónica Gordón-Alonso, María Angeles García-López, Hortensia de la Fuente, Carlos Martínez-A, Pilar Lauzurica, Francisco Sánchez-Madrid

×

Figure 6

Options: View larger image (or click on image) Download as PowerPoint
Effect of a blocking anti–TGF-β antibody in WT and CD69-deficient mice. ...
Effect of a blocking anti–TGF-β antibody in WT and CD69-deficient mice. (a) As shown in the left panel, CD69+/+ mice were treated from day 21 (second immunization) with the blocking anti–TGF-β antibody (squares), the isotype control IgG1 (triangles), or the carrier (inverted triangles). Paw inflammation measured with a precision caliper is expressed in millimeters of inflammation with respect to day 21. Results express the arithmetic mean ± SD of 12 mice per group in two independent experiments. On the right, analysis by quantitative real-time RT-PCR of mRNA from paws treated with isotype control antibody (white bars) or with anti–TGF-β (black bars) is shown. Each bar represents the arithmetic mean ± SD of 12 mice per group in two independent experiments. Results of each cytokine are normalized to GAPDH expression measured in parallel in each sample. *P < 0.01 versus control antibody (Mann-Whitney U test). (b) CD69–/– mice were treated as in a, paw inflammation was measured (left panel), and mRNA was determined (right panel) as above.