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性免疫通过激活异源记忆CD4 T细胞而具有保护作用。

先前的免疫如何影响免疫记忆的回忆和对相关黄病毒的保护在很大程度上尚不清楚，但是在一生中与多种黄病毒的接触越来越有可能。使用登革热病毒（DENV），黄热病病毒（YFV）和日本脑炎病毒（JEV）的顺序攻击，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。针对JEV的抗体可增强DENV复制；然而，JEV免疫在继发DENV1感染期间在体内具有保护作用，从而促进抗体亲和力的快速获得。从机制上讲，JEV免疫激活了树突状细胞和效应记忆T细胞，继发DENV1感染后，它们在引流淋巴结中形成了T滤泡辅助细胞表型。我们确定了交叉反应性抗原决定簇，可促进从黄病毒血清复合物交叉反应性记忆CD4 T细胞池中召回，并确认类似的血清复合物交叉反应性免疫发生在人类中。这些结果表明，针对共享CD4表位的黄病毒的顺序免疫应在随后的异源感染中促进保护。