Abstract
Decay accelerating factor (DAF) plays a complex role in the immune system through complement-dependent and -independent regulation of innate and adaptive immunity. Over the past five years there has been accumulating evidence for a significant role of DAF in negatively regulating adaptive T-cell responses and autoimmunity in both humans and experimental models. This review discusses the relationship between DAF and the complement system and highlights major advances in our understanding of the biology of DAF in human disease, particularly systemic lupus erythematosus. The role of DAF in regulation of idiopathic and environmentally induced systemic autoimmunity is discussed including studies showing that reduction or absence of DAF is associated with autoimmunity. In contrast, DAF-mediated T cell activation leads to cytokine expression consistent with T regulatory cells. This is supported by studies showing that interaction between DAF and its molecular partner, CD97, modifies expression of autoimmunity promoting cytokines. These observations are used to develop a hypothetical model to explain how DAF expression may impact T cell differentiation via interaction with CD97 leading to T regulatory cells, increased production of IL-10, and immune tolerance.
Highlights
Decay accelerating factor (DAF) was first described in 1969 in human erythrocytes that inhibited complement activation in vitro [1]
We have shown that activation of murine CD4+ T cells with antiCD3 and recombinant CD97 (rCD97) leads to a cytokine profile with increased IL-10 and reduced IL-17 and IL-21 compared to a more proinflammatory profile of elevated IFN-γ, IL-2, IL-4, IL10, IL-17, and IL-21 elicited by conventional costimulation by anti-CD3/anti-CD28 [19]
DAF serves a complex role in the immune system through complement-dependent and -independent functions in the regulation of innate and adaptive immunity
Summary
Decay accelerating factor (DAF) was first described in 1969 in human erythrocytes that inhibited complement activation in vitro [1]. DAF is encoded by a single gene which maps to q32 on chromosome 1 [10] It is widely expressed on the surface of all major circulating blood cells as well as epithelial and endothelial cells [9, 11]. Autoimmune Diseases activated by mitogens and in vitro stimulation with anti-DAF antibodies led to phosphatidylinositol-specific phospholipase C dependent T-cell proliferation [18]. This led to the hypothesis that an alternative function of DAF may be to regulate T-cell tolerance. DAF has been shown to negatively regulate a variety of autoimmune diseases including animal models of antiglomerular basement membrane glomerulonephritis, experimental autoimmune myasthenia gravis (EAMG), experimental autoimmune encephalomyelitis (EAE), cardiac allograft rejection, and idiopathic and induced models of systemic lupus erythematosus (SLE) [19,20,21,22,23,24]
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