Highlights • MERS-CoV structural proteins and ORFs potently induce T cell responses in mice • MERS-CoV-specific T cell epitope repertoires are identified in C57BL/6 and BALB/c mice • Airway ORF4b208-CD4+ and ORF5167-CD8+ T cells are optimal effector T cells • ORF4b208 and ORF5167-specific T cells protect mice against MERS-CoV infection Summary Since its initial emergence in 2012, MERS-CoV has remained endemic and a global health threat . While accessory proteins (ORFs) are known for immune evasion , their role in adaptive immunity is unexplored. This study systematically investigated T cell responses against MERS-CoV ORFs. We mapped epitope repertoires targeting structural proteins and ORFs in C57BL/6 and BALB/c mice , revealing that ORFs potently induced virus-specific T cells . Notably, ORF5 induced the dominant CD8+ T cell responses in BALB/c mice. Further analysis revealed that ORF4b208-specific CD4+ and ORF5167-specific CD8+ T cells in the respiratory...