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
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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

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Figure 8

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CD69 cross-linking induces TGF-β1 production in human synovial leukocyte...
CD69 cross-linking induces TGF-β1 production in human synovial leukocytes and in a human CD69 T cell stable transfectant. (a) Human synovial leukocytes from patients with RA were stained for CD69 (solid line, left panel) and isotype-matched antibody (dotted line, left panel). Synovial leukocytes were treated with anti-human CD69 (black bars) or an isotype-matched control antibody (white bars) in the presence (XL) or absence (–) of a cross-linking secondary antibody, and active and total TGF-β1 were determined (right). *P < 0.01 versus control antibody (Mann-Whitney U test). These results are representative of similar data obtained on synovial leukocytes from patients with reactive arthritis or ankylosing spondylitis. (b) Jurkat human T cell leukemic cell line (dotted line, left panel) and CD69 stable transfectants (solid line, left panel) were stained for CD69. Production of TGF-β1 but not TNF-α by CD69 engagement is shown in the right panel. The human T lymphoblastoid cell line Jurkat (JK) (white bars) and the stable transfectant expressing CD69 (JK-CD69) (black bars) were treated for 24 hours with cross-linked anti-CD69. Results in a and b are expressed as the arithmetic mean ± SD of four independent experiments. *P < 0.01 versus the parental JK cell line (Mann Whitney U test).