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

Chai Fen Soon,Dinler Amaral Antunes,Markus Cornberg,Pothakamuri Venkata Suneetha,Shihong Zhang,Margaret Sällberg Chen,Michael Peter Manns,Heiner Wedemeyer,Christian Schultze-Florey,Solaiman Raha,Immo Prinz

doi:10.3389/fimmu.2019.02076

Abstract

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.

Highlights

T cell immunotherapy was initially developed as a cancer treatment in late stage melanoma, to target tumor-associated antigens with the aim to control or eliminate tumor growth [1]
We aimed to study the possible cross-reactivity of a hepatitis E virus (HEV)-specific T cell receptors (TCRs) repertoire that was proposed as a candidate in T cell therapy in order to address the clinical concern of off-target specificity affecting self-peptides
Generation Sequencing on TCR repertoires proved the presence of oligoclonal α chains and one dominant β chain (TCRBV04-02) containing

Summary

Introduction

T cell immunotherapy was initially developed as a cancer treatment in late stage melanoma, to target tumor-associated antigens with the aim to control or eliminate tumor growth [1]. This approach is formulated based on immune-mediated T cell responses, the involvement of cytotoxic T lymphocytes harboring T cell receptors (TCR) that have specificities to target tumor antigens. We proposed that immunotherapy based on engineered T cells targeting HEV could be a novel approach to treat persistent HEV infection in solid organ transplant patients who are immunosuppressed

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