How previous immunity influences immune memory recall and protection against related flaviviruses is largely unknown, yet encounter with multiple flaviviruses in a lifetime is increasingly likely. Using sequential challenges with dengue virus (DENV), yellow fever virus (YFV), and Japanese encephalitis virus (JEV), we induced cross-reactive cellular and humoral immunity among flaviviruses from differing serocomplexes. Antibodies against JEV enhanced DENV replication; however, JEV immunity was protective in vivo during secondary DENV1 infection, promoting rapid gains in antibody avidity. Mechanistically, JEV immunity activated dendritic cells and effector memory T cells, which developed a T follicular helper cell phenotype in draining lymph nodes upon secondary DENV1 infection. We identified cross-reactive epitopes that promote recall from a pool of flavivirus serocomplex cross-reactive memory CD4 T cells and confirmed that a similar serocomplex cross-reactive immunity occurs in humans. These results show that sequential immunizations for flaviviruses sharing CD4 epitopes should promote protection during a subsequent heterologous infection.

中文翻译：

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黄病毒血清复合物交叉反应免疫通过激活异源记忆 CD4 T 细胞发挥保护作用。


先前的免疫如何影响免疫记忆回忆和针对相关黄病毒的保护在很大程度上尚不清楚，但一生中遇到多种黄病毒的可能性越来越大。通过登革热病毒（DENV）、黄热病病毒（YFV）和日本脑炎病毒（JEV）的连续攻击，我们诱导了来自不同血清复合物的黄病毒之间的交叉反应性细胞和体液免疫。抗 JEV 抗体增强 DENV 复制；然而，JEV免疫在继发DENV1感染期间在体内具有保护性，促进抗体亲和力的快速增加。从机制上讲，JEV免疫激活了树突状细胞和效应记忆T细胞，这些细胞在继发DENV1感染后在引流淋巴结中形成滤泡辅助T细胞表型。我们从黄病毒血清复合物交叉反应记忆 CD4 T 细胞库中鉴定出促进记忆的交叉反应表位，并证实人类中也存在类似的血清复合物交叉反应免疫。这些结果表明，共享 CD4 表位的黄病毒的顺序免疫应该可以促进随后的异源感染期间的保护。