M2e-tetramer-specific memory CD4 T cells are broadly protective against influenza infection
M2e-tetramer-specific memory CD4 T cells are broadly protective against influenza infection
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DOI：
10.1038/mi.2017.14
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发表时间：
2018-01-01
影响因子：
8
通讯作者：
Lycke, N.
中科院分区：
文献类型：
--
作者：
Eliasson, D. G.;Omokanye, A.;Lycke, N.
基质蛋白2外结构域（M2e）被认为是广泛保护的通用甲型流感疫苗的一个有吸引力的组成部分。在这里，我们挑战权威的观点，即抗M2e抗体是保护的主要效应器。用cta1 - 3m2e - dd产生的m2e特异性记忆CD4 T细胞鼻内免疫Balb/c小鼠，即使在完全没有抗体的情况下，也受到I-A(d)限制和严格保护，如在JhD小鼠中观察到的那样。尽管一些m2e -四聚体特异性记忆CD4 T细胞驻留在脾脏和淋巴结中，但大多数是驻留在肺部的Th17细胞，它们在病毒攻击感染时迅速扩增。事实上，尽管免疫IL-17A（-/-）小鼠的抗体水平相当，但与野生型小鼠相比，免疫IL-17A（-/-）小鼠的保护效果明显较差。同样，在同源Balb/B （H-2(B)）小鼠中也观察到较差的保护作用，这些小鼠不能产生m2e特异性CD4 T细胞，但表现出相当的抗体水平。肺驻留CD69(+) CD103（低）m2e特异性记忆CD4 T细胞为ab TCR+， 50%为Th17细胞，这些细胞与病毒攻击后早期中性粒细胞内流有关。过继转移的M2e记忆CD4 T细胞是强辅助T细胞，它加速了M2e的产生，但更重要的是加速了血凝素特异性IgG的产生。因此，我们首次证明m2e特异性记忆CD4 T细胞具有广泛的保护作用。
Matrix protein 2 ectodomain (M2e) is considered an attractive component of a broadly protective, universal influenza A vaccine. Here we challenge the canonical view that antibodies against M2e are the prime effectors of protection. Intranasal immunizations of Balb/c mice with CTA1-3M2e-DD-generated M2e-specific memory CD4 T cells that were I-A(d) restricted and critically protected against infection, even in the complete absence of antibodies, as observed in JhD mice. Whereas some M2e-tetramer-specific memory CD4 T cells resided in spleen and lymph nodes, the majority were lung-resident Th17 cells, that rapidly expanded upon a viral challenge infection. Indeed, immunized IL-17A(-/-) mice were significantly less well protected compared with wild-type mice despite exhibiting comparable antibody levels. Similarly, poor protection was also observed in congenic Balb/B (H-2(b)) mice, which failed to develop M2e-specific CD4 T cells, but exhibited comparable antibody levels. Lung-resident CD69(+) CD103(low) M2e-specific memory CD4 T cells were ab TCR+ and 50% were Th17 cells that were associated with an early influx of neutrophils after virus challenge. Adoptively transferred M2e memory CD4 T cells were strong helper T cells, which accelerated M2e- but more importantly also hemagglutinin-specific IgG production. Thus, for the first time we demonstrate that M2e-specific memory CD4 T cells are broadly protective.