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

Autor: Santamorena MM; Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School (MHH), Hannover, Germany., Tischer-Zimmermann S; Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School (MHH), Hannover, Germany., Bonifacius A; Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School (MHH), Hannover, Germany.; German Center for Infection Research (DZIF), Site Hannover-Braunschweig, Hannover, Germany., Mireisz CN; Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Wuerzburg, Wuerzburg, Germany., Costa B; Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany., Khan F; Immune Ageing and Chronic Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany., Kulkarni U; Immune Ageing and Chronic Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany., Lauruschkat CD; Department of Internal Medicine II, University Hospital Wuerzburg, Wuerzburg, Germany., Sampaio KL; Institute of Virology, Ulm University Medical Center, Ulm, Germany., Stripecke R; University of Cologne, Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, Center for Molecular Medicine Cologne (CMMC), Institute of Translational Immuno-oncology, Cologne, Germany.; German Center for Infections Research (DZIF) Bonn-Cologne, Cologne, Germany., Blasczyk R; Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School (MHH), Hannover, Germany., Maecker-Kolhoff B; German Center for Infection Research (DZIF), Site Hannover-Braunschweig, Hannover, Germany.; German Center for Infections Research (DZIF) Bonn-Cologne, Cologne, Germany.; Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany., Kraus S; Department of Internal Medicine II, University Hospital Wuerzburg, Wuerzburg, Germany., Schlosser A; Rudolf Virchow Center for Integrative and Translational Bioimaging, University of Wuerzburg, Wuerzburg, Germany., Cicin-Sain L; German Center for Infection Research (DZIF), Site Hannover-Braunschweig, Hannover, Germany.; Immune Ageing and Chronic Infection, Helmholtz Centre for Infection Research, Braunschweig, Germany.; Cluster of Excellence - Resolving Infection Susceptibility (RESIST, EXC 2155), Hannover Medical School, Hannover, Germany., Kalinke U; Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, Hannover, Germany.; Cluster of Excellence - Resolving Infection Susceptibility (RESIST, EXC 2155), Hannover Medical School, Hannover, Germany., Eiz-Vesper B; Institute of Transfusion Medicine and Transplant Engineering, Hannover Medical School (MHH), Hannover, Germany.; German Center for Infection Research (DZIF), Site Hannover-Braunschweig, Hannover, Germany.
Jazyk: angličtina
Zdroj: HLA [HLA] 2024 Jun; Vol. 103 (6), pp. e15541.
DOI: 10.1111/tan.15541
Abstrakt: 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 (A11 SAL ), 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 A11 SAL , with T-cell responses comparable to the immunodominant HLA-A*02:01-restricted HCMVpp65 NLV epitope. A11 SAL -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.
(© 2024 The Author(s). HLA: Immune Response Genetics published by John Wiley & Sons Ltd.)
Databáze: MEDLINE