W e tested 154 peptides spanning the entire length of core histones of nucleosomes for the ability to stimulate an anti-DNA autoantibody–inducing T helper (Th) clone, as well as CD4⁺ T-cell lines and T cells, in fresh PBMCs from 23 patients with lupus erythematosus. In contrast to normal T cells, lupus T cells responded strongly to certain histone peptides, irrespective of the patient’s disease status. Nucleosomal peptides in histone regions H2B_10–33, H4_16–39 (and overlapping H4_14–28), H4_71–94, and H3_91–105 (and overlapping H3_100–114) were recurrently recognized by CD4 T cells from the patients with lupus. Remarkably, these same peptides overlap with major epitopes for the Th cells that induce anti-DNA autoantibodies and nephritis in lupus-prone mice. We localized 2 other recurrent epitopes for human lupus T cells in H2A_34–48 and H4_49–63. All the T-cell autoepitopes have multiple HLA-DR binding motifs, and the epitopes are located in histone regions recognized by lupus autoantibodies, suggesting a basis for their immunodominance. Native nucleosomes and their peptides H4_16–39, H4_71–94, and H3_91–105 induced a stronger IFN-γ response, whereas others, particularly, H2A_34–48, favored an IL-10– and/or IL-4–positive T-cell response. The major autoepitopes may reveal the mechanism of autoimmune T-cell expansion and lead to antigen-specific therapy of human lupus.