Rowntree Louise C, Allen Lilith F, Hagen Ruth R, McQuilten Hayley A, Quadeer Ahmed A, Chaurasia Priyanka, Kaewpreedee Prathanporn, Lee Kelly W K, Cohen Carolyn A, Petersen Jan, Littler Dene R, Habel Jennifer R, Zhang Wuji, Cheng Samuel M S, Chan Ken Ka Pang, Kwok Janette S Y, Leung Kathy S M, Wu Joseph T, Lee Cheuk-Kwong, Davies Jane, Pannaraj Pia S, Kaity Allen E, Thomas Paul G, Tosif Shidan, Crawford Nigel W, Lappas Martha, Thevarajan Irani, Lewin Sharon R, Kent Stephen J, Juno Jennifer A, Bond Katherine A, Williamson Deborah A, Holmes Natasha E, Smibert Olivia C, Gordon Claire L, Trubiano Jason A, Kotsimbos Tom C, Cheng Allen C, Efstathiou Claudia, Turtle Lance, Thwaites Ryan S, Brightling Christopher E, Rossjohn Jamie, McKay Matthew R, Tian Jinmin, Liu William Jun, Gao George Fu, Xu Jianqing, Sonehara Kyuto, Ishii Ken J, Namkoong Ho, Okada Yukinori, Peiris Malik, Hui David S C, Poon Leo L M, Doherty Peter C, Nguyen Thi H O, Valkenburg Sophie A, Kedzierska Katherine
Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.
Department of Electronic and Computer Engineering, School of Engineering, Hong Kong University of Science and Technology, Hong Kong Special Administrative Region, Hong Kong, China.
Proc Natl Acad Sci U S A. 2025 Sep 9;122(36):e2503145122. doi: 10.1073/pnas.2503145122. Epub 2025 Sep 2.
Understanding host factors driving asymptomatic versus severe disease outcomes is of key importance if we are to control emerging and re-emerging viral infections. HLA-B15:01 has been associated with asymptomatic SARS-CoV-2 infection in nonhospitalized individuals of European ancestry, with protective immunity attributed to preexisting cross-reactive CD8 T-cells directed against HLA-B15:01-restricted Spike-derived S peptide (B15/SCD8 T-cells). However, fundamental questions remained on the abundance and clonotypic nature of CD8 T-cell responses in HLA-B15:01-positive patients who succumbed to life-threatening COVID-19. Here, we analyzed B15/SCD8 T-cell responses in COVID-19 patients from independent HLA-typed COVID-19 patient cohorts across three continents, Australia, Asia and Europe. We assessed B15/SCD8 T-cells in COVID-19 patients across disease outcomes ranging from asymptomatic to hospitalized critical illness. We found that severe/critical COVID-19 patients mounted B15/SCD8 T-cell responses lacking a highly expanded key public B15/SCD8 T-cell receptor (TCR; TRAV9-2/TRBV7-2) which recurred across multiple individuals in COVID-19 patients with a mild disease. Instead, B15/SCD8 T-cell responses in life-threatening disease had a prevalence of an alternate TCR clonotypic motif (TRAV38-2/DV8/TRBV20-1), potentially contributing, at least in part, to why B15/SCD8 T-cells in severe COVID-19 patients were less protective. Interestingly, the frequency, memory phenotype, and activation profiles of circulating B15/SCD8 T-cells did not differ across disease severity. Moreover, B15/SCD8 T-cells were better maintained into convalescence compared to other SARS-CoV-2-specificities. Our study thus provides evidence on the differential nature of the TCR clonal repertoire in 22.37% of HLA-B15:01-positive COVID-19 patients who developed severe or critical disease in our cohorts, comparing to HLA-B*15:01-expressing individuals with mild COVID-19.
如果我们想要控制新出现和再次出现的病毒感染，了解驱动无症状与严重疾病结果的宿主因素至关重要。HLA - B15:01与欧洲血统的非住院个体中无症状的SARS-CoV-2感染有关，保护性免疫归因于预先存在的针对HLA - B15:01限制性刺突衍生S肽的交叉反应性CD8 T细胞（B15/SCD8 T细胞）。然而，对于死于危及生命的COVID-19的HLA - B15:01阳性患者中CD8 T细胞反应的丰度和克隆型性质，仍存在一些基本问题。在这里，我们分析了来自澳大利亚、亚洲和欧洲三大洲独立进行HLA分型的COVID-19患者队列中的COVID-19患者的B15/SCD8 T细胞反应。我们评估了从无症状到住院危重症等不同疾病结果的COVID-19患者中的B15/SCD8 T细胞。我们发现，重症/危重症COVID-19患者产生的B15/SCD8 T细胞反应缺乏高度扩增的关键公共B15/SCD8 T细胞受体（TCR；TRAV9-2/TRBV7-2），而在轻症COVID-19患者中多个个体都出现这种受体。相反，危及生命疾病中的B15/SCD8 T细胞反应具有另一种TCR克隆型基序（TRAV38-2/DV8/TRBV20-1）的优势，这可能至少部分解释了为什么重症COVID-19患者中的B15/SCD8 T细胞保护性较差。有趣的是，循环B15/SCD8 T细胞的频率、记忆表型和激活谱在不同疾病严重程度之间没有差异。此外，与其他SARS-CoV-2特异性相比，B15/SCD8 T细胞在康复期能更好地维持。因此，我们的研究提供了证据，表明在我们的队列中，22.37%发展为重症或危重症疾病的HLA - B15:01阳性COVID-19患者与轻症COVID-19的HLA - B*15:01表达个体相比，TCR克隆库具有不同的性质。
