Mucosal Immunobiology and Vaccine Center (MIVAC), Department of Microbiology and Immunology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden.
Medical Biotechnology Center, VIB and Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
Mucosal Immunol. 2018 Jan;11(1):273-289. doi: 10.1038/mi.2017.14. Epub 2017 Mar 1.
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 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) mice, which failed to develop M2e-specific CD4 T cells, but exhibited comparable antibody levels. Lung-resident CD69 CD103 M2e-specific memory CD4 T cells were αβ 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.
基质蛋白 2 外结构域（M2e）被认为是一种有吸引力的、广泛保护性的通用流感 A 疫苗成分。在这里，我们挑战了一个传统观点，即针对 M2e 的抗体是主要的保护效应因子。用 CTA1-3M2e-DD 生成的 M2e 特异性记忆 CD4 T 细胞对 Balb/c 小鼠进行鼻内免疫，这些细胞受到 I-A 限制，能够在完全没有抗体的情况下（如 JhD 小鼠中观察到的那样）对感染产生关键保护作用。虽然一些 M2e-四聚体特异性记忆 CD4 T 细胞存在于脾脏和淋巴结中，但大多数是肺驻留的 Th17 细胞，在病毒感染挑战后迅速扩增。事实上，与野生型小鼠相比，免疫 IL-17A 小鼠的保护效果明显较差，尽管它们表现出类似的抗体水平。同样，在同基因 Balb/B（H-2）小鼠中也观察到保护效果不佳，这些小鼠未能产生 M2e 特异性 CD4 T 细胞，但表现出类似的抗体水平。肺驻留的 CD69 CD103 M2e 特异性记忆 CD4 T 细胞是 αβ TCR，其中 50%是 Th17 细胞，与病毒挑战后中性粒细胞的早期涌入有关。过继转移的 M2e 记忆 CD4 T 细胞是强大的辅助 T 细胞，它们加速了 M2e 特异性但更重要的是血凝素特异性 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。
