Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by anti-nuclear autoantibodies that cause damage to multiple organs and tissues. Intrinsic defects have been demonstrated in the lymphoid and myeloid cellular compartments, including T cells. Lupus susceptibility is mediated through the interplay of a large number of genes, most of which are still unidentified. Most of the genetic studies in both human patients and mouse models have addressed lupus susceptibility as a whole. More recently however, more attention has been paid to the inheritance of specific lupus-associated phenotypes. In this review, we summarized our results obtained with the Sle1 locus in the NZM2410 mouse model, which mediates the generation of anti-histone autoreactive T cells. Sle1, which is constituted of multiple genes, is the only known genomic region that is sufficient for the generation of autoreactive T cells. The identification of the corresponding genes will constitute a landmark for our understanding of the mechanisms of autoimmunity. Our results are discussed in the context of candidate genes and the role of T cells in systemic autoimmunity.