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Upstream position of proline defines peptide-HLA class I repertoire formation and CD8+ T cell responses

Hongo, Ayumi, Kanaseki, Takayuki, Tokita, Serina, Kochin, Vitaly, Miyamoto, Sho, Hashino, Yuiko, Codd, Amy, Kawai, Noriko, Nakatsugawa, Munehide, Hirohashi, Yoshihiko, Sato, Noriyuki and Torigoe, Toshihiko 2019. Upstream position of proline defines peptide-HLA class I repertoire formation and CD8+ T cell responses. Journal of Immunology 202 (10) , pp. 2849-2855. 10.4049/jimmunol.1900029
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Cytotoxic CD8+ T lymphocytes (CTLs) recognize peptides displayed by HLA class I molecules on cell surfaces, monitoring pathological conditions such as cancer. Difficulty in predicting HLA class I ligands is attributed to the complexity of the Ag processing pathway across the cytosol and the endoplasmic reticulum. By means of HLA ligandome analysis using mass spectrometry, we collected natural HLA class I ligands on a large scale and analyzed the source-protein sequences flanking the ligands. This comprehensive analysis revealed that the frequency of proline at amino acid positions 1–3 upstream of the ligands was selectively decreased. The depleted proline signature was the strongest among all the upstream and downstream profiles. Experiments using live cells demonstrated that the presence of proline at upstream positions 1–3 attenuated CTL responses against a model epitope. Other experiments, in which N-terminal–flanking Ag precursors were confined in the endoplasmic reticulum, demonstrated an inability to remove upstream prolines regardless of their positions, suggesting a need for synergistic action across cellular compartments for making the proline signature. Our results highlight, to our knowledge, a unique role and position of proline for inhibiting downstream epitope presentation, which provides a rule for defining natural peptide–HLA class I repertoire formation and CTL responses.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: American Association of Immunologists
ISSN: 0022-1767
Date of First Compliant Deposit: 15 August 2019
Date of Acceptance: 8 March 2019
Last Modified: 07 Jan 2022 18:35

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