Objective. Antigen-specific CD4+ T cells treated with DNA methylation inhibitors become autoreactive, suggesting a novel mechanism for autoimmunity. To test whether this mechanism might be involved in systemic lupus erythematosus (SLE), phenotypic markers for the autoreactive cells were sought.Methods. Cloned normal T cells were treated with the DNA methylation inhibitor 5-azacytidine (5-azaC) and studied for altered gene expression. T cells from patients with active SLE were then studied for a similar change in gene expression, and cells expressing the marker were tested for autoreactivity.Results. 5-azaC-treated normal T cells had increased CDlla (leukocyte function-associated antigen la) expression relative to other membrane molecules. A T cell subset with similar CDlla expression was found in patients with active SLE. This subset contained cells that spontaneously lysed autologous macrophages, with a specificity similar to that of 5-azaC-treated cells. Conclusion. The model of 5-azaC-induced autoreactivity may have relevance to SLE.Antigen-specific CD4+ T cell clones respond to autologous macrophages (Mgi) without antigen, following treatment with DNA methylation inhibitors such as 5-azacytidine (5-azaC). The response is inhibited by monoclonal antibodies (MAb) against CD3 and class I1 major histocompatibility complex (MHC) determinants, and occurs with autologous but not allogeneic Mgi (1,2), suggesting that the cells are responding to autologous class I1 MHC determinants via a pathway involving the antigedMHC receptor. Similar concentrations of 5-azaC alter gene expression in a wide range of cell types, including T cells (3-3, and the autoreactivity may be caused by changes in the expression of as-yet-unidentified genes involved in T cell activation.5-azaC-induced autoreactivity may have relevance to autoimmunity. Recent experiments have shown that murine T cells can become autoreactive following 5-azaC treatment, responding to and, intriguingly, lysing, syngeneic Mgi. Adoptive transfer of murine 5-azaC-treated cells induces an immune complex glomerulonephritis and anti-DNA antibodies in nonirradiated syngeneic mice (6). These findings suggest a novel model for systemic lupus erythematosus (SLE), in which T cell DNA hypomethylation could alter expression of crucial genes, resulting in T cell autoreactivity, and the autoreactive T cells could then produce a lupus-like illness. Reports that lupusinducing drugs inhibit T cell DNA methylation and induce autoreactivity (7) support this concept. Moreover, recent evidence indicates that T cell DNA methylation is impaired in patients with active SLE (8).