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 3

Options: View larger image (or click on image) Download as PowerPoint
Enhanced CII-specific immune response in CD69–/– mice. (a) Enlarged sple...
Enhanced CII-specific immune response in CD69–/– mice. (a) Enlarged spleens of CD69–/– compared with CD69+/+ mice. Scale bar: 1 cm. (b) Spleen weight and cell number (arithmetic mean ± SD) from CFA control and CII-immunized (CIA) CD69+/+ (white bars) and CD69–/– (black bars) mice are shown. *P < 0.01 versus WT immunized mice (Student’s t test). (c) Proliferation of spleen and LN cells from CII-immunized CD69+/+ (white bars) and CD69–/– (black bars) mice stimulated with different concentrations of inactivated CII (x axis). Data correspond to the arithmetic mean ± SD of [3H]TdR uptake in three independent experiments. *P < 0.01 versus CD69+/+ (Mann-Whitney U test). Sp, spleen. (d) Increments of CII-specific Th1-dependent isotypes in CD69–/– mice. CII-specific IgG1 and IgG2b (1:20,000 serum dilution), IgG2c and IgG3 (1:5,000 serum dilution), and IgM and IgA (1:200 serum dilution) antibody levels in sera collected at sacrifice (day 50) of CFA-treated control or CII-immunized (CIA) CD69+/+ (white bars) and CD69–/– (black bars) mice. Data are represented as the arithmetic mean ± SD of absorbance units at 495 nm in three separate experiments (10 mice per group per experiment). *P < 0.01 versus CD69+/+ (Student’s t test).