A consensus pool of T-cell epitopes from adenoviral antigens

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URI: http://hdl.handle.net/10900/128015
Dokumentart: PhDThesis
Date: 2022-06-10
Language: English
Faculty: 4 Medizinische Fakultät
Department: Medizin
Advisor: Stevanović, Stefan (Prof. Dr.)
Day of Oral Examination: 2022-05-10
DDC Classifikation: 500 - Natural sciences and mathematics
570 - Life sciences; biology
610 - Medicine and health
Other Keywords:
HAdV (human adenovirus)
HLA class II epitopes
HLA class I epitopes
peptide pools
antiviral T cells
epitope prediction
promiscuous CD4+ T-cell epitopes
License: http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=de http://tobias-lib.uni-tuebingen.de/doku/lic_mit_pod.php?la=en
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In immunocompromised patients, an adenoviral infection can turn into a fulminant progression of the disease, which often leads to death. Adoptive T-cell transfer was identified as a promising treatment approach. For the selection of virus-specific T cells, the knowledge of immunodominant epitopes is required. Within the scope of this project, HAdV-derived epitopes were identified and further investigated. We aimed to design one HLA class I and one HLA class II epitope cocktail that should lead to an immune response in ELISpot assays with randomly selected PBMC cultures. We compared the immune response to two HLA class I cocktails: one contained 24 HLA class I epitopes and the other contained the 15 epitopes with the highest recognition rates. The 24-peptides-cocktail elicited a IFN-γ response in 22 out of 25 PBMC cultures (88%). The 15 peptides cocktail led to a detectable IFN-γ response in 20 out of 25 PBMC cultures (80%). The 24-peptides-cocktail was always able to stimulate the PBMCs of donors, which were responsive to the 15 peptides cocktail. To date, there is no satisfying tool for promiscuous HLA class II epitope prediction. We performed a promiscuous epitope prediction on all 46 reviewed HAdV2 proteins from the Swiss-Prot database with SYFPEITHI and NetMHCIIpan 2.0. The top-ranked peptides and already published epitopes were synthesized and screened for immunogenicity in ELISpot assays. We designed an HLA class II peptide cocktail containing the 12 most immunogenic epitopes, proven to stimulate CD4+ T cells via ICS. Four epitopes are already published, seven of the epitopes were first identified by our prediction, and one epitope is an elongated HLA class I 10mer showing CD4+ T cell stimulation in ICS. The designed HLA class II cocktail could stimulate 31 out of 31 tested PBMC cultures (100%) in ELISpot assays. The assumption that the hexon protein is the main target of the immune response can be questioned as seven immunodominant HLA class II epitopes newly-discovered by the promiscuous prediction are derived from other proteins than the hexon. We identified an effective method for the prediction of promiscuous HLA class II epitopes. The combined SYFPEITHI/ NetMHCIIpan 2.0 prediction resulted in the synthesis of 27 peptides, from which nine (33.3%) were identified as immunodominant and twelve (44.4%) were categorized as subdominant epitopes. One of the dominant epitopes is already published. Six peptides (22.2%) were non-immunogenic. One immunodominant epitope was revealed as an HLA class I epitope in ICS.

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