Viral sequence determines HLA-E-restricted T cell recognition of hepatitis B surface antigen
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, Env<sub>371-379,</sub> 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 Env<sub>371-379</sub> peptides, we demonstrate that only the most stable Env<sub>371-379</sub> variant, L6I, elicits functional responses to a09b08-anti-CD3-redirected polyclonal T cells co-cultured with targets expressing endogenous HBsAg. Furthermore, HLA-E-Env<sub>371-379</sub> L6I-specific CD8<sup>+</sup> 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.
Authors
- M. Benjamin Hock (ORCID: https://orcid.org/0009-0007-4353-3738)
- Rachel L. Paterson (ORCID: https://orcid.org/0000-0001-6268-5947)
- Daniel P. Kay
- Tiaan Heunis (ORCID: https://orcid.org/0000-0003-1987-9484)
- Claire Barber (ORCID: https://orcid.org/0000-0001-9748-6665)
- Archana Jadhav (ORCID: https://orcid.org/0000-0001-9727-0493)
- Gavuthami Murugesan (ORCID: https://orcid.org/0000-0003-3422-4929)
- Luís F. Godinho (ORCID: https://orcid.org/0000-0002-2135-5148)
- Mary M. Connolly
- Andrew Knox (ORCID: https://orcid.org/0000-0002-1073-2091)
- Agatha Treveil
- Andrew Walker (ORCID: https://orcid.org/0000-0003-4715-4325)
- Dawn Gibbs‐Howe (ORCID: https://orcid.org/0000-0003-0842-4898)
- Sarah Leonard (ORCID: https://orcid.org/0000-0003-3752-7300)
- Rakesh Kulkarni (ORCID: https://orcid.org/0000-0002-1603-4139)
- Marcin Dembek (ORCID: https://orcid.org/0000-0003-2831-3335)
- V. Karuppiah (ORCID: https://orcid.org/0000-0002-9645-7958)
- Mariolina Salio (ORCID: https://orcid.org/0000-0002-4821-3801)
- Tressan Grant (ORCID: https://orcid.org/0009-0000-1177-9388)
- Lucy Dorrell
- Kate E. Atkin (ORCID: https://orcid.org/0009-0000-4214-9450)
- Carole Perot
- Richard J. Suckling (ORCID: https://orcid.org/0000-0002-6962-6533)
- Anshuk Sarkar
- V.F. Ilkow (ORCID: https://orcid.org/0000-0003-3968-465X)
- Wilawan Bunjobpol
- José Donoso (ORCID: https://orcid.org/0000-0001-8000-1262)
- Ritu Raj (ORCID: https://orcid.org/0000-0002-7623-9128)
- Ricardo J. Carreira (ORCID: https://orcid.org/0000-0002-7705-1354)
- Robert Pengelly (ORCID: https://orcid.org/0000-0002-4980-3707)
- Gwilym Philips
- Kafayat Ololade
Institutions
- Immunocore (United Kingdom) (GB)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-22
- DOI
- https://doi.org/10.1038/s41467-024-54378-9
- Citations
- 4
- Primary Topic
- Hepatitis B Virus Studies
- Type
- article
- Field-Weighted Citation Impact
- 1.55
Funders
- Cardiff University