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美国卫生研究院文献>PLoS Pathogens
>Generation of antigen-specific memory CD4 T cells by heterologous immunization enhances the magnitude of the germinal center response upon influenza infection
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Generation of antigen-specific memory CD4 T cells by heterologous immunization enhances the magnitude of the germinal center response upon influenza infection
Current influenza vaccine strategies have yet to overcome significant obstacles, including rapid antigenic drift of seasonal influenza viruses, in generating efficacious long-term humoral immunity. Due to the necessity of germinal center formation in generating long-lived high affinity antibodies, the germinal center has increasingly become a target for the development of novel or improvement of less-efficacious vaccines. However, there remains a major gap in current influenza research to effectively target T follicular helper cells during vaccination to alter the germinal center reaction. In this study, we used a heterologous infection or immunization priming strategy to seed an antigen-specific memory CD4+ T cell pool prior to influenza infection in mice to evaluate the effect of recalled memory T follicular helper cells in increased help to influenza-specific primary B cells and enhanced generation of neutralizing antibodies. We found that heterologous priming with intranasal infection with acute lymphocytic choriomeningitis virus (LCMV) or intramuscular immunization with adjuvanted recombinant LCMV glycoprotein induced increased antigen-specific effector CD4+ T and B cellular responses following infection with a recombinant influenza strain that expresses LCMV glycoprotein. Heterologously primed mice had increased expansion of secondary Th1 and Tfh cell subsets, including increased CD4+ TRM cells in the lung. However, the early enhancement of the germinal center cellular response following influenza infection did not impact influenza-specific antibody generation or B cell repertoires compared to primary influenza infection. Overall, our study suggests that while heterologous infection or immunization priming of CD4+ T cells is able to enhance the early germinal center reaction, further studies to understand how to target the germinal center and CD4+ T cells specifically to increase long-lived antiviral humoral immunity are needed.
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机译：目前的流感疫苗策略尚未克服产生有效长期体液免疫的重大障碍，包括季节性流感病毒的快速抗原漂移。由于生发中心形成在产生长寿命高亲和力抗体时的必要性，生发中心已日益成为开发新型或改进效果较差的疫苗的目标。然而，目前的流感研究仍然存在重大差距，无法在疫苗接种期间有效靶向滤泡辅助性 T 细胞以改变生发中心反应。在这项研究中，我们使用异源感染或免疫启动策略在小鼠流感感染前接种抗原特异性记忆 CD4 + T 细胞库，以评估回忆的记忆 T 滤泡辅助细胞在增加对流感特异性原代 B 细胞的帮助和增强中和抗体产生方面的作用。我们发现，急性淋巴细胞性脉络丛脑膜炎病毒 （LCMV） 鼻内感染的异源引发或佐剂重组 LCMV 糖蛋白的肌内免疫诱导了表达 LCMV 糖蛋白的重组流感毒株感染后抗原特异性效应子 CD4+ T 和 B 细胞反应增加。异源引发小鼠次级 Th1 和 Tfh 细胞亚群的扩增增加，包括肺中 CD4+ TRM 细胞的增加。然而，与原发性流感感染相比，流感感染后生发中心细胞反应的早期增强并不影响流感特异性抗体的产生或 B 细胞库。总体而言，我们的研究表明，虽然 CD4+ T 细胞的异源感染或免疫引发能够增强早期生发中心反应，但需要进一步研究来了解如何专门针对生发中心和 CD4 + T 细胞以提高长寿命抗病毒体液免疫。
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