Zhang Shihong, Bakshi Rakesh K, Suneetha Pothakamuri Venkata, Fytili Paraskevi, Antunes Dinler A, Vieira Gustavo F, Jacobs Roland, Klade Christoph S, Manns Michael P, Kraft Anke R M, Wedemeyer Heiner, Schlaphoff Verena, Cornberg Markus
Department of Gastroenterology, Hepatology, and Endocrinology, Hanover Medical School, Hanover, Germany Hanover Biomedical Research School, Hanover, Germany.
Department of Gastroenterology, Hepatology, and Endocrinology, Hanover Medical School, Hanover, Germany.
J Virol. 2015 Aug;89(16):8304-17. doi: 10.1128/JVI.00539-15. Epub 2015 Jun 3.
T cell responses play a critical role in controlling or clearing viruses. Therefore, strategies to prevent or treat infections include boosting T cell responses. T cells specific for various pathogens have been reported in unexposed individuals and an influence of such cells on the response toward vaccines is conceivable. However, little is known about their frequency, repertoire, and impact on vaccination. We performed a detailed characterization of CD8(+) T cells specific to a hepatitis C virus (HCV) epitope (NS3-1073) in 121 HCV-seronegative individuals. We show that in vitro HCV NS3-1073-specific CD8(+) T cell responses were rather abundantly detectable in one-third of HCV-seronegative individuals irrespective of risk factors for HCV exposure. Ex vivo, these NS3-1073-specific CD8(+) T cells were found to be both naive and memory cells. Importantly, recognition of various peptides derived from unrelated viruses by NS3-1073-specific CD8(+) T cells showed a considerable degree of T cell cross-reactivity, suggesting that they might in part originate from previous heterologous infections. Finally, we further provide evidence that preexisting NS3-1073-specific CD8(+) T cells can impact the T cell response toward peptide vaccination. Healthy, vaccinated individuals who showed an in vitro response toward NS3-1073 already before vaccination displayed a more vigorous and earlier response toward the vaccine.
Preventive and therapeutic vaccines are being developed for many viral infections and often aim on inducing T cell responses. Despite effective antiviral drugs against HCV, there is still a need for a preventive vaccine. However, the responses to vaccines can be highly variable among different individuals. Preexisting T cells in unexposed individuals could be one reason that helps to explain the variable T cell responses to vaccines. Based on our findings, we suggest that HCV CD8(+) T cells are abundant in HCV-seronegative individuals but that their repertoire is highly diverse due to the involvement of both naive precursors and cross-reactive memory cells of different specificities, which can influence the response to vaccines. The data may emphasize the need to personalize immune-based therapies based on the individual's T cell repertoire that is present before the immune intervention.
T细胞应答在控制或清除病毒方面发挥着关键作用。因此，预防或治疗感染的策略包括增强T细胞应答。在未接触过病原体的个体中已报道了针对各种病原体的T细胞，并且可以想象此类细胞对疫苗应答的影响。然而，关于它们的频率、库以及对疫苗接种的影响知之甚少。我们对121名丙型肝炎病毒（HCV）血清阴性个体中针对HCV表位（NS3 - 1073）的CD8(+) T细胞进行了详细表征。我们发现，在三分之一的HCV血清阴性个体中，无论HCV暴露的危险因素如何，体外均可大量检测到HCV NS3 - 1073特异性CD8(+) T细胞应答。在体外，这些NS3 - 1073特异性CD8(+) T细胞被发现既有初始细胞又有记忆细胞。重要的是，NS3 - 1073特异性CD8(+) T细胞对源自无关病毒的各种肽的识别显示出相当程度的T细胞交叉反应性，这表明它们可能部分源自先前的异源感染。最后，我们进一步提供证据表明，预先存在的NS3 - 1073特异性CD8(+) T细胞可影响对肽疫苗接种的T细胞应答。在接种疫苗之前就对NS3 - 1073表现出体外应答的健康接种个体，对疫苗表现出更强烈且更早的应答。
针对许多病毒感染正在研发预防性和治疗性疫苗，且通常旨在诱导T细胞应答。尽管有针对HCV的有效抗病毒药物，但仍需要预防性疫苗。然而，不同个体对疫苗的应答可能差异很大。未接触过病原体的个体中预先存在的T细胞可能是有助于解释对疫苗的T细胞应答差异的一个原因。基于我们的发现，我们认为HCV CD8(+) T细胞在HCV血清阴性个体中很丰富，但由于不同特异性的初始前体细胞和交叉反应性记忆细胞的参与，它们的库高度多样化，这可能影响对疫苗的应答。这些数据可能强调了基于免疫干预前个体存在的T细胞库进行个性化免疫治疗的必要性。
