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

IF 14.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Nature Communications Pub Date : 2024-11-22 DOI:10.1038/s41467-024-54378-9

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

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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, Env_371-379, 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 Env_371-379 peptides, we demonstrate that only the most stable Env_371-379 variant, L6I, elicits functional responses to a09b08-anti-CD3-redirected polyclonal T cells co-cultured with targets expressing endogenous HBsAg. Furthermore, HLA-E-Env_371-379 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.

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病毒序列决定了 HLA-E 限制性 T 细胞对乙型肝炎表面抗原的识别能力

非多态性 HLA-E 分子为慢性传染病提供了新的通用免疫治疗方法。慢性乙型肝炎病毒（HBV）感染的部分原因是乙型肝炎病毒包膜（Env）蛋白乙型肝炎表面抗原（HBsAg）水平升高导致的T细胞功能障碍。我们在此报告了 HLA-E 结合 HBsAg 多肽 Env371-379 的三种基因型变体的特征，这些变体是通过生物信息学预测确定的，并通过生化和细胞测定进行了验证。我们使用可溶性亲和力增强型 T 细胞受体（TCR）（a09b08）-抗-CD3 双特异性分子来探查 Env371-379 多肽的 HLA-E 呈递，结果表明只有最稳定的 Env371-379 变体 L6I 能引起与表达内源性 HBsAg 的靶细胞共培养的 a09b08-抗-CD3-定向多克隆 T 细胞的功能性应答。此外，HLA-Env371-379 L6I 特异性 CD8+ T 细胞在体外诱导后，可在 HBV 纯合供体和慢性 HBV 患者中检测到。总之，我们为 HLA-E 介导的 HBV Env 多肽呈现提供了证据，并强调了病毒突变对 pHLA-E 分子稳定性和靶向性的影响。

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来源期刊

Nature Communications Biological Science Disciplines-

CiteScore

24.90

自引率

2.40%

发文量

6928

审稿时长

3.7 months

期刊介绍： Nature Communications, an open-access journal, publishes high-quality research spanning all areas of the natural sciences. Papers featured in the journal showcase significant advances relevant to specialists in each respective field. With a 2-year impact factor of 16.6 (2022) and a median time of 8 days from submission to the first editorial decision, Nature Communications is committed to rapid dissemination of research findings. As a multidisciplinary journal, it welcomes contributions from biological, health, physical, chemical, Earth, social, mathematical, applied, and engineering sciences, aiming to highlight important breakthroughs within each domain.