Hepatitis E Virus (HEV)-Specific T Cell Receptor Cross-Recognition

TY - JOUR

T1 - Hepatitis E Virus (HEV)-Specific T Cell Receptor Cross-Recognition

T2 - Implications for Immunotherapy

AU - Soon, Chai Fen

AU - Zhang, Shihong

AU - Suneetha, Pothakamuri Venkata

AU - Antunes, Dinler Amaral

AU - Manns, Michael Peter

AU - Raha, Solaiman

AU - Schultze-Florey, Christian

AU - Prinz, Immo

AU - Wedemeyer, Heiner

AU - Sällberg Chen, Margaret

AU - Cornberg, Markus

PY - 2019

Y1 - 2019

N2 - 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.

AB - 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.

KW - Amino Acid Motifs/immunology

KW - Amino Acid Sequence

KW - CD8-Positive T-Lymphocytes/immunology

KW - Cross Reactions/immunology

KW - Epitopes/immunology

KW - HLA-A2 Antigen/immunology

KW - Hepatitis E/immunology

KW - Hepatitis E virus/immunology

KW - Humans

KW - Immunotherapy/methods

KW - Protein Binding

KW - Receptors, Antigen, T-Cell/immunology

KW - Receptors, Antigen, T-Cell, alpha-beta/immunology

KW - T-Lymphocytes, Cytotoxic/immunology

U2 - 10.3389/fimmu.2019.02076

DO - 10.3389/fimmu.2019.02076

M3 - SCORING: Journal article

C2 - 31552033

VL - 10

SP - 2076

JO - FRONT IMMUNOL

JF - FRONT IMMUNOL

SN - 1664-3224

ER -