tetano
Editor, Senior Moderator
Front Immunol
. 2026 Apr 27:17:1758642.
doi: 10.3389/fimmu.2026.1758642. eCollection 2026.
N-terminal pyroglutamylation of an HLA-A24-restricted immunodominant epitope enhances SARS-CoV-2-specific T-cell responses
Yoshiki Aritsu[SUP] 1 [/SUP], Masahiro Kitabatake[SUP] 2 [/SUP], Amiri Kurose[SUP] 3 [/SUP], Hiroshi Hamana[SUP] 4 [/SUP], Takeshi Nakama[SUP] 1 [/SUP], Kyoko Yamada[SUP] 1 [/SUP], Ryutaro Furukawa[SUP] 2 [/SUP], Noriko Ouji-Sageshima[SUP] 2 [/SUP], Atsushi Hara[SUP] 2 [/SUP], Kaito Yasuike[SUP] 2 [/SUP], Suzu Itami[SUP] 5 [/SUP], Huanyu Li[SUP] 1 [/SUP], Keiko Udaka[SUP] 6 [/SUP], Hiroyuki Kishi[SUP] 4 [/SUP], Takamasa Ueno[SUP] 1 [/SUP], So Nakagawa[SUP] 7 [/SUP], Toshihiro Ito[SUP] 2 [/SUP], Norihito Kawashita[SUP] 8 [/SUP], Mizuki Kitamatsu[SUP] 3 [/SUP], Chihiro Motozono[SUP] 1 [/SUP]
Affiliations
T-cell responses play a critical role in the control of SARS-CoV-2 infections. Here, we examined the T-cell response to a conserved, immunodominant HLA-A*24:02-restricted SARS-CoV-2 spike protein epitope, QI9/A24 (QYIKWPWYI; residues 1208-1216). TCR repertoire analysis revealed that QI9/A24-specific T cells are highly diverse, with 219 clonotypes isolated and 169 αβ TCR pairs identified in six donors. To further characterize this response, we evaluated T-cell recognition of alanine-substituted and homologous coronavirus-derived peptides, using a TCR reconstitution system, and found that QI9/A24 TCRs tolerated numerous substitutions at the N-terminus and position 3. During peptide synthesis, we unexpectedly discovered that an N-terminally pyroglutamylated QI9/A24 peptide (pyrQI9) exhibited increased protease resistance, compared with the unmodified peptide. Further analysis revealed that the pyrQI9 peptide was recognized with higher sensitivity than the wild-type sequence and efficiently induced antigen-specific T-cell responses at low concentrations in both vaccinated and convalescent HLA-A*24:02-positive individuals. Moreover, immunization of HLA-A24 transgenic mice with the pyrQI9 peptide elicited antigen-specific T-cell responses more efficiently than the wild-type peptide and conferred superior T-cell-mediated protection. Together, our findings suggest that subtle modifications of antigenic peptides at a tolerable site in the N-terminus with pyroglutamate can enhance T-cell immunity in SARS-CoV-2 infection, providing critical insights into the design of next-generation T-cell-based vaccines against viral infections.
Keywords: SARS-CoV-2; T cell; TCR (T cell receptor); peptide vaccine; pyroglutamate.
. 2026 Apr 27:17:1758642.
doi: 10.3389/fimmu.2026.1758642. eCollection 2026.
N-terminal pyroglutamylation of an HLA-A24-restricted immunodominant epitope enhances SARS-CoV-2-specific T-cell responses
Yoshiki Aritsu[SUP] 1 [/SUP], Masahiro Kitabatake[SUP] 2 [/SUP], Amiri Kurose[SUP] 3 [/SUP], Hiroshi Hamana[SUP] 4 [/SUP], Takeshi Nakama[SUP] 1 [/SUP], Kyoko Yamada[SUP] 1 [/SUP], Ryutaro Furukawa[SUP] 2 [/SUP], Noriko Ouji-Sageshima[SUP] 2 [/SUP], Atsushi Hara[SUP] 2 [/SUP], Kaito Yasuike[SUP] 2 [/SUP], Suzu Itami[SUP] 5 [/SUP], Huanyu Li[SUP] 1 [/SUP], Keiko Udaka[SUP] 6 [/SUP], Hiroyuki Kishi[SUP] 4 [/SUP], Takamasa Ueno[SUP] 1 [/SUP], So Nakagawa[SUP] 7 [/SUP], Toshihiro Ito[SUP] 2 [/SUP], Norihito Kawashita[SUP] 8 [/SUP], Mizuki Kitamatsu[SUP] 3 [/SUP], Chihiro Motozono[SUP] 1 [/SUP]
Affiliations
- PMID: 42125653
- PMCID: PMC13158186
- DOI: 10.3389/fimmu.2026.1758642
T-cell responses play a critical role in the control of SARS-CoV-2 infections. Here, we examined the T-cell response to a conserved, immunodominant HLA-A*24:02-restricted SARS-CoV-2 spike protein epitope, QI9/A24 (QYIKWPWYI; residues 1208-1216). TCR repertoire analysis revealed that QI9/A24-specific T cells are highly diverse, with 219 clonotypes isolated and 169 αβ TCR pairs identified in six donors. To further characterize this response, we evaluated T-cell recognition of alanine-substituted and homologous coronavirus-derived peptides, using a TCR reconstitution system, and found that QI9/A24 TCRs tolerated numerous substitutions at the N-terminus and position 3. During peptide synthesis, we unexpectedly discovered that an N-terminally pyroglutamylated QI9/A24 peptide (pyrQI9) exhibited increased protease resistance, compared with the unmodified peptide. Further analysis revealed that the pyrQI9 peptide was recognized with higher sensitivity than the wild-type sequence and efficiently induced antigen-specific T-cell responses at low concentrations in both vaccinated and convalescent HLA-A*24:02-positive individuals. Moreover, immunization of HLA-A24 transgenic mice with the pyrQI9 peptide elicited antigen-specific T-cell responses more efficiently than the wild-type peptide and conferred superior T-cell-mediated protection. Together, our findings suggest that subtle modifications of antigenic peptides at a tolerable site in the N-terminus with pyroglutamate can enhance T-cell immunity in SARS-CoV-2 infection, providing critical insights into the design of next-generation T-cell-based vaccines against viral infections.
Keywords: SARS-CoV-2; T cell; TCR (T cell receptor); peptide vaccine; pyroglutamate.