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Acquired thrombotic thrombocytopenic purpura is a rare and severe disease characterized by auto-antibodies directed against "A Disintegrin And Metalloproteinase with Thrombospondin type 1 repeats, 13 member" (ADAMTS13), a plasma protein involved in hemostasis. Involvement of CD4 T cells in the pathogenesis of the disease is suggested by the IgG isotype of the antibodies. However, the nature of the CD4 T-cell epitopes remains poorly characterized. Here, we determined the HLA-DR-restricted CD4 T-cell epitopes of ADAMTS13. Candidate T-cell epitopes were predicted and binding affinities were confirmed in competitive enzyme-linked immunosorbent assays. ADAMTS13-reactive CD4 T-cell hybridomas were generated following immunization of HLA-DR1 transgenic mice (Sure-L1 strain) and used to screen the candidate epitopes. We identified the ADAMTS13 peptide as the single immunodominant HLA-DR1-restricted CD4 T-cell epitope. This peptide is located in the CUB2 domain of ADAMTS13. It was processed by dendritic cells, stimulated CD4 T cells from Sure-L1 mice and was recognized by CD4 T cells from an HLA-DR1-positive patient with acute thrombotic thrombocytopenic purpura. Interestingly, the ADAMTS13 peptide demonstrated promiscuity towards HLA-DR11 and HLA-DR15. Our work paves the way towards the characterization of the ADAMTS13-specific CD4 T-cell response in patients with thrombotic thrombocytopenic purpura using ADAMTS13-loaded HLA-DR tetramers.