Generation of Norovirus-Specific T cells from Human Donors with extensive Cross-Reactivity to variant sequences: implications for Immunotherapy

Hanajiri, R., Sani, G.M., Saunders, D., Hanley, P.J., Chopra, A., Mallal, S.A., Sosnovtsev, S.V., Cohen, J.I., Green, K.Y., Bollard, C.M. and Keller, M.D. (2019) Generation of Norovirus-Specific T cells from Human Donors with extensive Cross-Reactivity to variant sequences: implications for Immunotherapy. The Journal of Infectious Diseases, 221 (4). pp. 578-588.

Abstract

Background
Chronic norovirus infection in immunocompromised patients can be severe, and presently there is no effective treatment. Adoptive transfer of virus-specific T cells has proven to be safe and effective for the treatment of many viral infections, and this could represent a novel treatment approach for chronic norovirus infection. Hence, we sought to generate human norovirus-specific T cells (NSTs) that can recognize different viral sequences.

Methods
Norovirus-specific T cells were generated from peripheral blood of healthy donors by stimulation with overlapping peptide libraries spanning the entire coding sequence of the norovirus genome.

Results
We successfully generated T cells targeting multiple norovirus antigens with a mean 4.2 ± 0.5-fold expansion after 10 days. Norovirus-specific T cells comprised both CD4+ and CD8+ T cells that expressed markers for central memory and effector memory phenotype with minimal expression of coinhibitory molecules, and they were polyfunctional based on cytokine production. We identified novel CD4- and CD8-restricted immunodominant epitopes within NS6 and VP1 antigens. Furthermore, NSTs showed a high degree of cross-reactivity to multiple variant epitopes from clinical isolates.

Conclusions
Our findings identify immunodominant human norovirus T-cell epitopes and demonstrate that it is feasible to generate potent NSTs from third-party donors for use in antiviral immunotherapy.

Item Type:	Journal Article
Murdoch Affiliation(s):	Institute for Immunology and Infectious Diseases
Publisher:	Oxford University Press
Copyright:	© 2019 The Author(s).
URI:	http://researchrepository.murdoch.edu.au/id/eprint/54739

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