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Background  All four dengue virus (DV) serotypes (D1V, D2V, D3V and D4V) can cause a series of disorders, ranging from mild dengue fever (DF) to severe dengue hemorrhagic fever and dengue shock syndrome (DHF/DSS). Previous studies have revealed that DV serotype-specific CD8 +  T cells are involved in controlling DV infection. Serotype cross-reactive CD8 +  T-cells may contribute to the immunopathogenesis of DHF/DSS. The aim of the study was to identify HLA-A*0201-binding peptides from four DV serotypes. We then examined their immunogenicity  in vivo  and cross-reactivity within heterologous peptides.    Methods  D1V-derived candidate CD8 +  T-cell epitopes were synthesized and evaluated for their affinity to the HLA-A*0201 molecule. Variant peptides representing heterologous D2V, D3V, D4V serotypes were synthesized. The immunogenicity of the high-affinity peptides were evaluated in HLA-A*0201 transgenic mice.    Results  Of the seven D1V-derived candidate epitopes [D1V-NS4a 56–64 (MLLALIAVL), D1V-C 46–54 (LVMAFMAFL), D1V-NS4b 562–570 (LLATSIFKL), D1V-NS2a 169–177 (AMVLSIVSL), D1V-NS4a 140–148 (GLLFMILTV), D1V-NS2a 144–152 (QLWAALLSL) and D1V-NS4b 183–191 (LLMRTTWAL)], three peptides [D1V-NS4a 140–148 , D1V-NS2a 144–152  and D1V-NS4b 183–191 ] had a high affinity for HLA-A*0201 molecules. Moreover, their variant peptides for D2V, D3V and D4V [D2V-NS4a 140–148 (AILTVVAAT), D3V-NS4a 140-148 (GILTLAAIV), D4V-NS4a 140-148 (TILTIIGLI), D2V-NS2a 144–152 (QLAVTIMAI), D3V-NS2a 144–152 (QLWTALVSL), D4V-NS2a 143–151 (QVGTLALSL), D2V-NS4b 182–190 (LMMRTTWAL) ,  D3V-NS4b 182–190  (LLMRTSWAL) and D4V-NS4b 179–187 (LLMRTTWAF)] also had a high affinity for HLA-A*0201 molecules. Furthermore, CD8 +  T cells directed to these twelve peptides were induced in HLA-A*0201 transgenic mice following immunization with these peptides. Additionally, cross-reactivity within four peptides (D1V-NS4b 183–191 , D2V-NS4b 182–190,  D3V-NS4b 182–190  and D4V-NS4b 179–187 ) was observed.    Conclusions  Two novel serotype-specific HLA-A*0201-restricted CD8 +  T-cell epitopes (NS4a 140-148  and NS2a 144–152 ) and one cross-reactive HLA-A*0201-restricted CD8 +  T-cell epitopes which is similar to a previously identified epitope were identified in D1V-D4V. Combining prediction algorithms and HLA transgenic mice is an effective strategy to identify HLA-restricted epitopes. Serotype-specific epitopes would be used to determine the protective role of serotype-specific CD8 +  T cells, while cross-reactive epitopes may provide assistance in exploring the role of serotype cross-reactive CD8 +  T cells in the immunopathogenesis of DHF/DSS.

HLA-A*0201-restricted CD8+T-cell epitopes identified in dengue viruses