Characterization of a library of 20 HBV-specific MHC class II-restricted T cell receptors
CD4+ T cells play an important role in the immune response against cancer and infectious diseases. However, mechanistic details of their helper function in hepatitis B virus (HBV) infection in particular, or their advantage for adoptive T cell therapy remain poorly understood as experimental and the...
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Elsevier
2021
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oai:doaj.org-article:6e1a360fffa84d45a1983f0217ef04272021-11-14T04:33:20ZCharacterization of a library of 20 HBV-specific MHC class II-restricted T cell receptors2329-050110.1016/j.omtm.2021.10.012https://doaj.org/article/6e1a360fffa84d45a1983f0217ef04272021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2329050121001698https://doaj.org/toc/2329-0501CD4+ T cells play an important role in the immune response against cancer and infectious diseases. However, mechanistic details of their helper function in hepatitis B virus (HBV) infection in particular, or their advantage for adoptive T cell therapy remain poorly understood as experimental and therapeutic tools are missing. Therefore, we identified, cloned, and characterized a comprehensive library of 20 MHC class II-restricted HBV-specific T cell receptors (TCRs) from donors with acute or resolved HBV infection. The TCRs were restricted by nine different MHC II molecules and specific for eight different epitopes derived from intracellularly processed HBV envelope, core, and polymerase proteins. Retroviral transduction resulted in a robust expression of all TCRs on primary T cells. A high functional avidity was measured for all TCRs specific for epitopes S17, S21, S36, and P774 (half-maximal effective concentration [EC50] <10 nM), or C61 and preS9 (EC50 <100 nM). Eight TCRs recognized peptide variants of HBV genotypes A to D. Both CD4+ and CD8+ T cells transduced with the MHC II-restricted TCRs were polyfunctional, producing interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, and granzyme B (GrzB), and killed peptide-loaded target cells. Our set of MHC class II-restricted TCRs represents an important tool for elucidating CD4+ T cell help in viral infection with potential benefit for T cell therapy.Sophia SchreiberMelanie HonzWeeda MamozaiPeter KurktschievMatthias SchiemannKlaus WitterEugene MooreChristina ZielinskiAlessandro SetteUlrike ProtzerKarin WisskirchenElsevierarticleMHC class II-restricted T cell receptorsCD4+ T cellschronic hepatitis Badoptive T cell therapyhepatocellular carcinomaT cell helpGeneticsQH426-470CytologyQH573-671ENMolecular Therapy: Methods & Clinical Development, Vol 23, Iss , Pp 476-489 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
MHC class II-restricted T cell receptors CD4+ T cells chronic hepatitis B adoptive T cell therapy hepatocellular carcinoma T cell help Genetics QH426-470 Cytology QH573-671 |
| spellingShingle |
MHC class II-restricted T cell receptors CD4+ T cells chronic hepatitis B adoptive T cell therapy hepatocellular carcinoma T cell help Genetics QH426-470 Cytology QH573-671 Sophia Schreiber Melanie Honz Weeda Mamozai Peter Kurktschiev Matthias Schiemann Klaus Witter Eugene Moore Christina Zielinski Alessandro Sette Ulrike Protzer Karin Wisskirchen Characterization of a library of 20 HBV-specific MHC class II-restricted T cell receptors |
| description |
CD4+ T cells play an important role in the immune response against cancer and infectious diseases. However, mechanistic details of their helper function in hepatitis B virus (HBV) infection in particular, or their advantage for adoptive T cell therapy remain poorly understood as experimental and therapeutic tools are missing. Therefore, we identified, cloned, and characterized a comprehensive library of 20 MHC class II-restricted HBV-specific T cell receptors (TCRs) from donors with acute or resolved HBV infection. The TCRs were restricted by nine different MHC II molecules and specific for eight different epitopes derived from intracellularly processed HBV envelope, core, and polymerase proteins. Retroviral transduction resulted in a robust expression of all TCRs on primary T cells. A high functional avidity was measured for all TCRs specific for epitopes S17, S21, S36, and P774 (half-maximal effective concentration [EC50] <10 nM), or C61 and preS9 (EC50 <100 nM). Eight TCRs recognized peptide variants of HBV genotypes A to D. Both CD4+ and CD8+ T cells transduced with the MHC II-restricted TCRs were polyfunctional, producing interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, and granzyme B (GrzB), and killed peptide-loaded target cells. Our set of MHC class II-restricted TCRs represents an important tool for elucidating CD4+ T cell help in viral infection with potential benefit for T cell therapy. |
| format |
article |
| author |
Sophia Schreiber Melanie Honz Weeda Mamozai Peter Kurktschiev Matthias Schiemann Klaus Witter Eugene Moore Christina Zielinski Alessandro Sette Ulrike Protzer Karin Wisskirchen |
| author_facet |
Sophia Schreiber Melanie Honz Weeda Mamozai Peter Kurktschiev Matthias Schiemann Klaus Witter Eugene Moore Christina Zielinski Alessandro Sette Ulrike Protzer Karin Wisskirchen |
| author_sort |
Sophia Schreiber |
| title |
Characterization of a library of 20 HBV-specific MHC class II-restricted T cell receptors |
| title_short |
Characterization of a library of 20 HBV-specific MHC class II-restricted T cell receptors |
| title_full |
Characterization of a library of 20 HBV-specific MHC class II-restricted T cell receptors |
| title_fullStr |
Characterization of a library of 20 HBV-specific MHC class II-restricted T cell receptors |
| title_full_unstemmed |
Characterization of a library of 20 HBV-specific MHC class II-restricted T cell receptors |
| title_sort |
characterization of a library of 20 hbv-specific mhc class ii-restricted t cell receptors |
| publisher |
Elsevier |
| publishDate |
2021 |
| url |
https://doaj.org/article/6e1a360fffa84d45a1983f0217ef0427 |
| work_keys_str_mv |
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