Peptide S598 Q600F

JHMV is a member of the same group of coronaviruses as two pathogenic human coronaviruses associated with severe respiratory disease. The CD8 T cell response to JHMV in C57BL/6 (B6) mice is directed at two epitopes, spanning residues 510–518 and 598–605 of the surface glycoprotein (CSLWNGPHL, S510, H-2Db–restricted and RCQIFANI, S598, H-2Kb–restricted). Epitope S510 is immunodominant, induces a high–functional avidity response, and in some settings undergoes mutation as part of viral evasion of the T cell response. Epitope S598 is subdominant and binds with lower affinity to the MHCI molecule than peptide S510. Furthermore, the low–functional avidity response to epitope S598 is unable to protect mice after infection with virus mutated in S510. With the goal of enhancing the S598-specific response, it was optimized peptide binding to Kb by changing a secondary anchor residue at position three of the epitope from Gln to Tyr to match the consensus motif for Kb binding (RCYIFANI; Q600Y). The modified peptide enhanced the stability of pMHCI and induced CD8 T cells with higher functional avidity toward the native form of the S598 epitope. A substantial fraction (∼35%) of the responding T cells recognized only the variant Q600Y epitope. This level of cross-reactivity would be unsuitable in a clinical setting because part of the T cell response would be ineffectual (i.e., these T cells would recognize only the heteroclitic peptide and would not contribute to a protective immune response) and could potentially recognize a self-epitope.