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
{"title":"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","authors":"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":"10.1038/s41467-024-54378-9","DOIUrl":null,"url":null,"abstract":"<p>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.</p>","PeriodicalId":19066,"journal":{"name":"Nature Communications","volume":"11 1","pages":""},"PeriodicalIF":14.7000,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Viral sequence determines HLA-E-restricted T cell recognition of hepatitis B surface antigen\",\"authors\":\"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\":\"10.1038/s41467-024-54378-9\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p>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.</p>\",\"PeriodicalId\":19066,\"journal\":{\"name\":\"Nature Communications\",\"volume\":\"11 1\",\"pages\":\"\"},\"PeriodicalIF\":14.7000,\"publicationDate\":\"2024-11-22\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Nature Communications\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://doi.org/10.1038/s41467-024-54378-9\",\"RegionNum\":1,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Nature Communications","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1038/s41467-024-54378-9","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
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, 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.
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.
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