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Abstract: An epitope-based vaccine is a promising option for treating Helicobacter pylori (H. pylori) infection. Epitope mapping is the first step in designing an epitope-based vaccine. A pivotal role of CD4+ T cells in protection against H. pylori has been accepted, but few Th epitopes have been identified. In this study, two novel UreB CD4+ T cell epitopes were identified using PBMCs obtained from two H. pylori infected subjects. We determined the restriction molecules by antibody blocking and used various Epstein–Barr virus-transformed B lymphocyte cell lines (BLCLs) with different HLA alleles as APCs to present peptides to CD4+ T cells. These epitopes were DRB1*1404-restricted UreB373–385 and DRB1*0803-restricted UreB438–452. The T cells specific to these epitopes not only recognized autologous DCs loaded with recombinant UreB but also those pulsed with H. pylori whole cell lysates, suggesting that these epitope peptides are naturally processed. These epitopes have important value for designing an effective H. pylori vaccine. [Copyright &y& Elsevier]