Viral sequence determines HLA-E-restricted T cell recognition of hepatitis B surface antigen

Gavuthami Murugesan, Rachel L. Paterson, Rakesh Kulkarni, Veronica Ilkow, Richard J. Suckling, Mary M. Connolly, Vijaykumar Karuppiah, Robert Pengelly, Archana Jadhav, Jose Donoso, Tiaan Heunis, Wilawan Bunjobpol, Gwilym Philips, Kafayat Ololade, Daniel Kay, Anshuk Sarkar, Claire Barber, Ritu Raj, Carole Perot, Tressan Grant, Agatha Treveil, Andrew Walker, Marcin Dembek, Dawn Gibbs-Howe, Miriam Hock, Ricardo J. Carreira, Kate E. Atkin, Lucy Dorrell, Andrew Knox, Sarah Leonard, Mariolina Salio and Luis F. Godinho ()
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Gavuthami Murugesan: 92 Park Drive
Rachel L. Paterson: 92 Park Drive
Rakesh Kulkarni: 92 Park Drive
Veronica Ilkow: 92 Park Drive
Richard J. Suckling: 92 Park Drive
Mary M. Connolly: 92 Park Drive
Vijaykumar Karuppiah: 92 Park Drive
Robert Pengelly: 92 Park Drive
Archana Jadhav: 92 Park Drive
Jose Donoso: 92 Park Drive
Tiaan Heunis: 92 Park Drive
Wilawan Bunjobpol: 92 Park Drive
Gwilym Philips: 92 Park Drive
Kafayat Ololade: 92 Park Drive
Daniel Kay: 92 Park Drive
Anshuk Sarkar: 92 Park Drive
Claire Barber: 92 Park Drive
Ritu Raj: 92 Park Drive
Carole Perot: 92 Park Drive
Tressan Grant: 92 Park Drive
Agatha Treveil: 92 Park Drive
Andrew Walker: 92 Park Drive
Marcin Dembek: 92 Park Drive
Dawn Gibbs-Howe: 92 Park Drive
Miriam Hock: 92 Park Drive
Ricardo J. Carreira: 92 Park Drive
Kate E. Atkin: 92 Park Drive
Lucy Dorrell: 92 Park Drive
Andrew Knox: 92 Park Drive
Sarah Leonard: 92 Park Drive
Mariolina Salio: 92 Park Drive
Luis F. Godinho: 92 Park Drive

Nature Communications, 2024, vol. 15, issue 1, 1-15

Abstract: Abstract The non-polymorphic HLA-E molecule offers opportunities for new universal immunotherapeutic approaches to chronic infectious diseases. Chronic Hepatitis B virus (HBV) infection is driven in part by T cell dysfunction due to elevated levels of the HBV envelope (Env) protein hepatitis B surface antigen (HBsAg). Here we report the characterization of three genotypic variants of an HLA-E-binding HBsAg peptide, Env371-379, identified through bioinformatic predictions and verified by biochemical and cellular assays. Using a soluble affinity-enhanced T cell receptor (TCR) (a09b08)-anti-CD3 bispecific molecule to probe HLA-E presentation of the Env371-379 peptides, we demonstrate that only the most stable Env371-379 variant, L6I, elicits functional responses to a09b08-anti-CD3-redirected polyclonal T cells co-cultured with targets expressing endogenous HBsAg. Furthermore, HLA-E-Env371-379 L6I-specific CD8+ T cells are detectable in HBV-naïve donors and people with chronic HBV after in vitro priming. In conclusion, we provide evidence for HLA-E-mediated HBV Env peptide presentation, and highlight the effect of viral mutations on the stability and targetability of pHLA-E molecules.

Date: 2024
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DOI: 10.1038/s41467-024-54378-9

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