Hepatitis E Virus (HEV)-Specific T Cell Receptor Cross-Recognition: Implications for Immunotherapy

Frontiers in Immunology

卷:10

Markus Cornberg²  Chai Fen Soon³  Michael Peter Manns³  Dinler Amaral Antunes⁴  Heiner Wedemeyer⁶  Pothakamuri Venkata Suneetha⁷  Shihong Zhang⁷  Christian Schultze-Florey⁸  Solaiman Raha¹⁰  Immo Prinz¹⁰  Margaret Sällberg Chen¹¹ 

[1] 0Centre for Individualised Infection Medicine, Hanover, Germany;

[2] 1Helmholtz Centre for Infection Research, Braunschweig, Germany;

[3] Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hanover, Germany;

[4] Department of Computer Science, Rice University, Houston, TX, United States;

[5] Department of Dental Medicine and Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden;

[6] Department of Gastroenterology and Hepatology, University Clinic Essen, Essen, Germany;

[7] Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hanover, Germany;

[8] Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hanover, Germany;

[9] German Center for Infection Research, Partner Site Hannover-Braunschweig, Hanover, Germany;

[10] Hannover Medical School, Institute of Immunology, Hanover, Germany;

[11] Shanghai Tenth People's Hospital, Tongji University, Shanghai, China;

关键词: CD8+ T cells;    cross-reactivity;    T cell therapy;    immunotherapy;    T cell receptor (TCR);    TCR redirection;   

DOI  :  10.3389/fimmu.2019.02076

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown