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Engineered HCMV‐infected APCs enable the identification of new immunodominant HLA‐restricted epitopes of anti‐HCMV T‐cell immunity.

Authors :
Santamorena, Maria Michela
Tischer‐Zimmermann, Sabine
Bonifacius, Agnes
Mireisz, Chiara Noemi‐Marie
Costa, Bibiana
Khan, Fawad
Kulkarni, Upasana
Lauruschkat, Chris David
Sampaio, Kerstin Laib
Stripecke, Renata
Blasczyk, Rainer
Maecker‐Kolhoff, Britta
Kraus, Sabrina
Schlosser, Andreas
Cicin‐Sain, Luka
Kalinke, Ulrich
Eiz‐Vesper, Britta
Source :
HLA: Immune Response Genetics; Jun2024, Vol. 103 Issue 6, p1-27, 27p
Publication Year :
2024

Abstract

Complications due to HCMV infection or reactivation remain a challenging clinical problem in immunocompromised patients, mainly due to insufficient or absent T‐cell functionality. Knowledge of viral targets is crucial to improve monitoring of high‐risk patients and optimise antiviral T‐cell therapy. To expand the epitope spectrum, genetically‐engineered dendritic cells (DCs) and fibroblasts were designed to secrete soluble (s)HLA‐A*11:01 and infected with an HCMV mutant lacking immune evasion molecules (US2‐6 + 11). More than 700 HLA‐A*11:01‐restricted epitopes, including more than 50 epitopes derived from a broad range of HCMV open‐reading‐frames (ORFs) were identified by mass spectrometry and screened for HLA‐A*11:01‐binding using established prediction tools. The immunogenicity of the 24 highest scoring new candidates was evaluated in vitro in healthy HLA‐A*11:01+/HCMV+ donors. Thus, four subdominant epitopes and one immunodominant epitope, derived from the anti‐apoptotic protein UL36 and ORFL101C (A11SAL), were identified. Their HLA‐A*11:01 complex stability was verified in vitro. In depth analyses revealed highly proliferative and cytotoxic memory T‐cell responses against A11SAL, with T‐cell responses comparable to the immunodominant HLA‐A*02:01‐restricted HCMVpp65NLV epitope. A11SAL‐specific T cells were also detectable in vivo in immunosuppressed transplant patients and shown to be effective in an in vitro HCMV‐infection model, suggesting their crucial role in inhibiting viral replication and improvement of patient's outcome. The developed in vitro pipeline is the first to utilise genetically‐engineered DCs to identify naturally presented immunodominant HCMV‐derived epitopes. It therefore offers advantages over in silico predictions, is transferable to other HLA alleles, and will significantly expand the repertoire of viral targets to improve therapeutic options. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
20592302
Volume :
103
Issue :
6
Database :
Complementary Index
Journal :
HLA: Immune Response Genetics
Publication Type :
Academic Journal
Accession number :
178211521
Full Text :
https://doi.org/10.1111/tan.15541