Vector-Mediated Delivery of Human Major Histocompatibility Complex-I into Hepatocytes Enables Investigation of T Cell Receptor-Redirected Hepatitis B Virus-Specific T Cells in Mice, and in Macaque Cell Cultures

Julia Festag, Marvin M. Festag, Theresa Asen, Jochen M. Wettengel, Martin A. Mück-Häusl, Shaheed Abdulhaqq, Christiane Stahl-Hennig, Jonah B. Sacha, Benjamin J. Burwitz, Ulrike Protzer, Karin Wisskirchen

Research output: Contribution to journalArticlepeer-review

Abstract

Adoptive T cell therapy using natural T cell receptor (TCR) redirection is a promising approach to fight solid cancers and viral infections in liver and other organs. However, clinical efficacy of such TCR+-T cells has been limited so far. One reason is that syngeneic preclinical models to evaluate safety and efficacy of TCR+-T cells are missing. We, therefore, developed an efficient viral vector strategy mediating expression of human major histocompatibility complex (MHC)-I in hepatocytes, which allows evaluation of TCR-T cell therapies targeting diseased liver cells. We designed adeno-associated virus (AAV) and adenoviral vectors encoding either the human-mouse chimeric HLA-A*02-like molecule, or fully human HLA-A*02 and human b2 microglobulin (hb2m). Upon transduction of murine hepatocytes, the HLA-A*02 construct proved superior in terms of expression levels, presentation of endogenously processed peptides and activation of murine TCR+-T cells grafted with HLA-A*02-restricted, hepatitis B virus (HBV)-specific TCRs. In vivo, these T cells elicited effector function, controlled HBV replication, and reduced HBV viral load and antigen expression in livers of those mice that had received AAV-HBV and AAV-HLA-A*02. We then demonstrated the broad utility of this approach by grafting macaque T cells with the HBV-specific TCRs and enabling them to recognize HBV-infected primary macaque hepatocytes expressing HLA-A*02 upon adenoviral transduction. In conclusion, AAV and adenovirus vectors are suitable for delivery of HLA-A*02 and hb2m into mouse and macaque hepatocytes. When recognizing their cognate antigen in HLA-A*02-transduced mouse livers or on isolated macaque hepatocytes, HLA-A*02-restricted, HBV-specific TCR+-T cells become activated and exert antiviral effector functions. This approach is applicable to any MHC restriction and target disease, paving the way for safety and efficacy studies of human TCR-based therapies in physiologically relevant preclinical animal models.

Original languageEnglish
Pages (from-to)1204-1218
Number of pages15
JournalHuman Gene Therapy
Volume34
Issue number23-24
DOIs
StatePublished - 1 Dec 2023
Externally publishedYes

Keywords

  • AAV vector
  • HLA-A*02
  • MHC-I molecule
  • adoptive T cell therapy
  • hepatitis B virus
  • primary macaque hepatocytes
  • primary mouse hepatocytes

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