Major peptide autoepitopes for nucleosome-specific T cells of human lupus

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Abstract
We 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 H2B10–33, H416–39 (and overlapping H414–28), H471–94, and H391–105 (and overlapping H3100–114) 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 H2A34–48 and H449–63. 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 H416–39, H471–94, and H391–105 induced a stronger IFN-γ response, whereas others, particularly, H2A34–48, 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.