Nature Communications (Nov 2024)

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,
  • Luis F. Godinho

DOI
https://doi.org/10.1038/s41467-024-54378-9
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 15

Abstract

Read online

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.