Sircy Linda M, Ramstead Andrew G, Gibbs Lisa C, Joshi Hemant, Baessler Andrew, Mena Ignacio, García-Sastre Adolfo, Emerson Lyska L, Fairfax Keke C, Williams Matthew A, Hale J Scott
Department of Pathology, University of Utah, Salt Lake City, Utah, United States of America.
Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, United States of America.
PLoS Pathog. 2024 Sep 16;20(9):e1011639. doi: 10.1371/journal.ppat.1011639. eCollection 2024 Sep.
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.
目前的流感疫苗策略在产生有效的长期体液免疫方面尚未克服重大障碍，包括季节性流感病毒的快速抗原漂移。由于生发中心的形成对于产生长寿的高亲和力抗体是必要的，生发中心越来越成为开发新型疫苗或改进低效疫苗的靶点。然而，目前的流感研究在疫苗接种过程中有效靶向滤泡辅助性T细胞以改变生发中心反应方面仍存在重大差距。在本研究中，我们使用异源感染或免疫启动策略在小鼠感染流感之前预先建立抗原特异性记忆CD4+ T细胞库，以评估回忆性记忆滤泡辅助性T细胞对流感特异性初级B细胞增加的辅助作用以及增强中和抗体产生的效果。我们发现，用急性淋巴细胞性脉络丛脑膜炎病毒（LCMV）鼻内感染或用佐剂重组LCMV糖蛋白进行肌肉内免疫进行异源启动，可诱导在用表达LCMV糖蛋白的重组流感毒株感染后增加抗原特异性效应CD4+ T细胞和B细胞反应。异源启动的小鼠次级Th1和Tfh细胞亚群的扩增增加，包括肺中CD4+ TRM细胞增加。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未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启动能够增强早期生发中心反应，但仍需要进一步研究以了解如何特异性靶向生发中心和CD4+ T细胞以增加长寿的抗病毒体液免疫。
