Division of Immunity and Pathogenesis, Burnett School of Biomedical Sciences College of Medicine, University of Central Florida, Orlando, FL.
J Immunol. 2023 Mar 1;210(5):628-639. doi: 10.4049/jimmunol.2200393.
Overcoming interfering impacts of pre-existing immunity to generate universally protective influenza A virus (IAV)-specific T cell immunity through vaccination is a high priority. In this study, we passively transfer varied amounts of H1N1-IAV-specific immune serum before H1N1-IAV infection to determine how different levels of pre-existing Ab influence the generation and protective potential of heterosubtypic T cell responses in a murine model. Surprisingly, IAV nucleoprotein-specific CD4 and CD8 T cell responses are readily detected in infected recipients of IAV-specific immune serum regardless of the amount transferred. When compared with responses in control groups and recipients of low and intermediate levels of convalescent serum, nucleoprotein-specific T cell responses in recipients of high levels of IAV-specific serum, which prevent overt weight loss and reduce peak viral titers in the lungs, are, however, markedly reduced. Although detectable at priming, this response recalls poorly and is unable to mediate protection against a lethal heterotypic (H3N2) virus challenge at later memory time points. A similar failure to generate protective heterosubtypic T cell immunity during IAV priming is seen in offspring of IAV-primed mothers that naturally receive high titers of IAV-specific Ab through maternal transfer. Our findings support that priming of protective heterosubtypic T cell responses can occur in the presence of intermediate levels of pre-existing Ab. These results have high relevance to vaccine approaches aiming to incorporate and evaluate cellular and humoral immunity towards IAV and other viral pathogens against which T cells can protect against variants escaping Ab-mediated protection.
通过接种疫苗克服对先前存在的免疫的干扰影响，从而产生普遍保护性的甲型流感病毒 (IAV) 特异性 T 细胞免疫是当务之急。在这项研究中，我们在感染 H1N1-IAV 之前通过被动转移不同量的 H1N1-IAV 特异性免疫血清，以确定先前存在的 Ab 水平如何影响异源 T 细胞反应的产生和保护潜力在小鼠模型中。令人惊讶的是，感染 H1N1-IAV 特异性免疫血清的受者中，无论转移的量如何，都可以轻易检测到 IAV 核蛋白特异性 CD4 和 CD8 T 细胞反应。与对照组和低中和中等水平恢复期血清的受者相比，高剂量 IAV 特异性血清的受者中核蛋白特异性 T 细胞反应明显降低，高剂量 IAV 特异性血清可预防明显的体重减轻和降低肺部的峰值病毒滴度，但仍可检测到。尽管在启动时可检测到，但该反应的回忆很差，并且无法在稍后的记忆时间点针对致命的异型 (H3N2) 病毒挑战进行保护。在 IAV 启动期间，IAV 启动的母亲的后代中也会出现类似的无法产生保护性异源 T 细胞免疫的情况，这些母亲通过母体转移自然获得高滴度的 IAV 特异性 Ab。我们的研究结果表明，在存在中间水平的先前存在的 Ab 的情况下，可以启动保护性异源 T 细胞反应。这些结果与旨在针对逃避 Ab 介导保护的 T 细胞可保护的 IAV 和其他病毒病原体的细胞和体液免疫纳入和评估的疫苗方法具有高度相关性。
