Objective. Investigators in this study undertook to determine whether in vitro antigen-responsive immune (polyomavirus T antigen [T-ag]-specific) and autoimmune (histone-specific) T cells from normal individuals share structural and genetic characteristics with those from patients with systemic lupus erythematosus (SLE).Methods. Histone-specific T cells were generated by stimulation of peripheral blood mononuclear cells (PBMCs) with nucleosome-T-ag complexes and were subsequently maintained by pure histones. T-agspecific T cell clones were initiated and maintained by T-ag. The frequencies of circulating histone-and T-agspecific T cells were determined in healthy individuals and in SLE patients by limiting dilution of PBMCs. T cell receptor (TCR) gene usage and variable-region structures were determined by complementary DNA sequencing. These sequences were compared between T-ag-and histone-specific T cells and between normal individuals and SLE patients for each specificity.Results. Individual in vitro-expanded histoneand T-ag-specific T cells from normal individuals displayed identical TCR V ␣ and/or V ␤ chain third complementarity-determining region (CDR3) sequences, indicating that they were clonally expanded in vivo. The frequencies of in vitro antigen-responsive T-ag-or histone-specific T cells from normal individuals were similar to those from SLE patients. Although heterogeneous for variable-region structure and gene usage, histone-specific T cells from healthy individuals and SLE patients selected aspartic and/or glutamic acids at positions 99 and/or 100 of the V ␤ CDR3 sequence. Conclusion. Autoimmune T cells from healthy individuals can be activated by nucleosome-T-ag complexes and maintained by histones in vitro. Such T cells possessed TCR structures similar to those from SLE patients, demonstrating that T cell autoimmunity to nucleosomes may be a latent property of the normal immune system.Experimental results consistently demonstrate that pathogenic autoimmune anti-DNA antibodies are secondary, antigen-driven, CD4ϩ T cell-dependent immune responses initiated by DNA itself (1-5). Since DNA most likely is not presented by antigen-presenting cells (APCs) in the context of HLA class II molecules, the contemporary paradigm favors DNA binding proteins as a sine qua non for generating T helper cell stimuli in the autoimmune anti-DNA antibody response (3,5,6). Such a hapten-carrier model, implying DNAspecific B cells and protein-specific T cells, enables the understanding of the molecular and the cellular basis for an immunoglobulin class switch and affinity maturation of anti-single-stranded DNA and anti-double-stranded DNA (anti-dsDNA) antibodies. Experimental and clinical results demonstrating that T cells specific for self or non-self DNA binding proteins may provide help for DNA-specific B cells support a model consistent with cognate B cell-T cell interaction (2,3,(6)(7)(8). So far, however, it is unclear how self-specific T cells may be initially activated. A priori, one would expect, for example, nuc...