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CD 69 downregulates autoimmune reactivity through active transforming growth factor-β production in collagen-induced arthritis

The Journal of Clinical Investigation | September 2003 | Volume 112 | Number 6 Introduction CD69 is a leukocyte receptor transiently induced after activation (1–5) that is detected on small subsets of T and B cells in peripheral lymphoid tissues from healthy subjects (6). In addition, CD69 is persistently expressed in leukocyte infiltrates of various chronic inflammatory diseases (7, 8). Several reports have indicated that CD69 is involved in the in vitro activation of bone marrow–derived cells (2, 3, 9). Nevertheless, the functional role of this molecule could be different in vivo. Transgenic CD69 mice accumulate mature thymocytes at the medulla of the thymus (10, 11). In this regard, we have found that hematopoietic cell development, thymocyte positive and negative selection, and T cell maturation is normal in CD69–/– mice under physiological conditions (12). In addition, NK cell–dependent tumor rejection is favored in the absence of CD69 (13). However, the functional role of CD69 expressed by T cells and macrophages at inflammatory sites and in autoimmune processes has not been explored. Murine collagen-induced arthritis (CIA) is a T cell–dependent, antibody-mediated autoimmune disease directed against cartilage type II collagen (CII) (14). CIA is a widely accepted experimental model of inflammatory joint disease, mainly rheumatoid arthritis (RA) (14). A strong inflammatory cell infiltrate with proliferation of synovial cell lining (pannus) as well as cartilage and bone destruction are seen in CIA and RA. In addition, proinflammatory cytokines (IL-1β, TNF-α) and various chemokines are involved in the pathogenesis of the immune-mediated joint damage observed in CIA and RA (15). TGF-β1 is considered an anti-inflammatory cytokine, and null mutations of the TGF-β1 gene result in a severe multiorgan inflammatory disorder that is rapidly lethal (16, 17). TGF-β1 downregulates proinflammatory cytokine production (18, 19) and exerts a clear-cut protective effect on CIA (20, 21). However, intra-articular injection of high amounts of this cytokine also induces synovitis and fibroblast hyperplasia (22), and systemic administration may be deleterious (23). The balance between proinflammatory and anti-inflammatory cytokines is thus crucial to the outcome of the disease (15). Therefore, tissue levels CD69 downregulates autoimmune reactivity through active transforming growth factor-β production in collagen-induced arthritis