1 Dept. of Infection and immunity, Joint Res. Center for Human Retrovirus infection, Kumamoto Univ. 2 Dept. of Infection and Immunity, Sch. of Med., Cardiff Univ.3 Dept. of Immunology, Faculty of Med., Univ. Toyama4 Dept. of Applied Chemistry, Faculty of Sci. and Eng., Kindai Univ.5 Dept. of Immunology, Kochi Univ.The molecular mechanism of SARS-CoV-2 spike L452R escape from HLA-Although the SARS-CoV-2 variants retain susceptibility to cellular immunity, the cross-reactivity of antigen-specific T cells towards variants remains unclear. Our study identified NF9 (S448-456: NYNYLYRLF), a SARS-CoV-2 spike-derived epitope presented by HLA-A*24:02, as immunodominant in both convalescent and vaccinated donors in IFN-γ ELISpot with overlapping spike peptides. Single-cell TCR analysis of NF9-specific T cells revealed public TCR clonotypes comprising TRAV12 and TRBV6 were identified in both groups. Notably, the naturally occurring L452R mutation, found in Delta/Omicron BA.5 variants, is located at the 5th position within the NF9 epitope. We established TCR-transfected NFAT-Luciferase reporter cells and tested the recognition of NF9-specific TCRs towards NF9-5X variant peptides. These TCRs exhibited weak recognition of the NF9-5R variant. To understand the molecular basis, we solved the crystal structure of the public TCR-NF9/A24 complex. This revealed that the L452R mutation disrupts the interaction of the CDR3α loop with a key contact residue, Y453, leading directly to a loss of TCR recognition. Further analysis of Delta/Omicron BA.5 convalescents using HLA-tetramers demonstrated the absence of variant (NF9-5R)-specific T cells. In summary, we highlight the molecular basis of the SARS-CoV-2 L452R escape from HLA-A24 restricted T cell immunity. A*24:02-restricted CD8+ T cells○Takeshi Nakama1 Aaron Wall2 Hiroshi Hamana3 Yoshiki Aritsu1 Toong Seng Tan1Mako Toyoda1 Yoshihiko Goto1 Huanyu Li1 Mizuki Kitamatsu4 Keiko Udaka5Pierre J Rizkallah2 Hiroyuki Kishi3 Takamasa Ueno1Andrew K Sewell2 Chihiro Motozono1 41P 011
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