The cause of systemic lupus erythematosus (SLE) is unknown. IFN-a has been suggested as a causative agent of SLE; however, it was not proven, and to what extent and how IFN-a contributes to the disease is unknown. We studied the contribution of IFN-a to SLE by generating inducible IFN-a transgenic mice and directly show that conditional upregulation of IFN-a alone induces a typical manifestation of SLE in the mice not prone to autoimmunity, such as serum immune complex, autoantibody against dsDNA (anti-dsDNA Ab), and the organ manifestations classical to SLE, such as immune complex-deposited glomerulonephritis, classical splenic onion-skin lesion, alopecia, epidermal liquefaction, and positive lupus band test of the skin. In the spleen of mice, activated effector CD4 T cells, IFN-g-producing CD8 T cells, B220 + CD86 + cells, and CD11c + CD86 + cells were increased, and the T cells produced increased amounts of IL-4, IL-6, IL-17, and IFN-g and decreased IL-2. In particular, activated CD3 + CD4 2 CD8 2 doublenegative T cells positive for TCRab, B220, CD1d-teteramer, PD-1, and Helios (that produced increased amounts of IFN-g, IL-4, IL-17, and TNF-a) were significantly expanded. They infiltrated into kidney and induced de novo glomerulonephritis and alopecia when transferred into naive recipients. Thus, sole upregulation of IFN-a is sufficient to induce SLE, and the double-negative T cells expanded by IFN-a are directly responsible for the organ manifestations, such as lupus skin disease or nephritis.
