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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.02076

Hepatitis E virus (HEV)-specific T cell receptor cross-recognition: Implications for immunotherapy

 Chai Fen Soon1,  Shihong Zhang1, 2, Pothakamuri Venkata Suneetha1,  Dinler A. Amaral Antunes3,  Michael P. Manns1, Solaiman Raha4, Christian Schultze-Florey4, 5,  Immo Prinz4, Heiner Wedemeyer1, 6, 7,  Margaret Sallberg Chen8, 9, 10 and  Markus Cornberg1, 6, 11, 12*
  • 1Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Germany
  • 2Fred Hutchinson Cancer Research Center, United States
  • 3Department of Computer Science, George R. Brown School of Engineering, Rice University, United States
  • 4Institute of Immunology, Hannover Medical School, Germany
  • 5Abteilung für Hämatologie, Hämostaseologie, Onkologie und Stammzelltransplantation, Medizinische Hochschule Hannover, Germany
  • 6German Center for Infection Research (DZIF), partner-site Hannover-Braunschweig, Germany
  • 7Department of Gastroenterology and Hepatology, University Hospital Essen, Germany
  • 8Department of Dental Medicine, Karolinska Institutet, Sweden
  • 9Department of Laboratory Medicine, Karolinska Institutet, Sweden
  • 10Shanghai Tenth People's Hospital, Tongji University, China
  • 11Zentrum für Individualisierte Infektionsmedizin, Helmholtz-Zentrum für Infektionsforschung (HZI), Germany
  • 12Helmholtz Center for Infection Research, Helmholtz Association of German Research Centers (HZ), Germany

T cell immunotherapy is a concept developed for the treatment of cancer and infectious diseases, based on cytotoxic T lymphocytes to target tumor- or pathogen-specific antigens. Antigen-specificity of the T cell receptors (TCRs) is an important selection criterion in the developmental design of immunotherapy. However, off-target specificity is a possible autoimmunity concern if the engineered antigen-specific T cells are cross-reacting to self-peptides in-vivo. In our recent work, we identified several hepatitis E virus (HEV)-specific TCRs as potential candidates to be developed into T cell therapy to treat chronic hepatitis E. One of the identified TCRs, targeting a HLA-A2-restricted epitope at the RNA-dependent RNA polymerase (HEV-1527: LLWNTVWNM), possessed a unique multiple glycine motif in the TCR-β CDR3, which might be a factor inducing cross-reactivity. The aim of our study was to explore if this TCR could cross-recognize self-peptides to underlay autoimmunity. Indeed, we found that this HEV-1527-specific TCR could also cross-recognize an apoptosis-related epitope, Nonmuscle Myosin Heavy Chain 9 (MYH9-478: QLFNHTMFI). While this TCR had dual specificities to both viral epitope and a self-antigen by double Dextramer binding, it was selectively functional against HEV-1527 but not activated against MYH9-478. The consecutive glycine motif in β chain may be the reason promoting TCR binding promiscuity to recognize a secondary target, thereby facilitating cross-recognition. In conclusion, candidate TCRs for immunotherapy development should be screened for autoimmune potential, especially when the TCRs exhibit unique sequence pattern.

Keywords: CD8+ T cells, cross-reactivity, T cell therapy, Immunotherapy, T cell receptor (TCR), TCR redirection, Hepatitis E virus (HEV)

Received: 26 Jun 2019; Accepted: 16 Aug 2019.

Copyright: © 2019 Soon, Zhang, Suneetha, Amaral Antunes, Manns, Raha, Schultze-Florey, Prinz, Wedemeyer, Sallberg Chen and Cornberg. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Markus Cornberg, Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, 30625, Germany,