Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America.
PLoS One. 2010 May 11;5(5):e10583. doi: 10.1371/journal.pone.0010583.
Memory CD8 T cells to influenza A viruses are widely detectable in healthy human subjects and broadly cross-reactive for serologically distinct influenza A virus subtypes. However, it is not clear to what extent such pre-existing cellular immunity can provide cross-subtype protection against novel emerging influenza A viruses.
METHODOLOGY/PRINCIPAL FINDINGS: We show in the mouse model that naturally occurring sequence variations of the conserved nucleoprotein of the virus significantly impact cross-protection against lethal disease in vivo. When priming and challenge viruses shared identical sequences of the immunodominant, protective NP(366)/D(b) epitope, strong cross-subtype protection was observed. However, when they did not share complete sequence identity in this epitope, cross-protection was considerably reduced. Contributions of virus-specific antibodies appeared to be minimal under these circumstances. Detailed analysis revealed that the magnitude of the memory CD8 T cell response triggered by the NP(366)/D(b) variants was significantly lower than those triggered by the homologous NP(366)/D(b) ligand. It appears that strict specificity of a dominant public TCR to the original NP(366)/D(b) ligand may limit the expansion of cross-reactive memory CD8 T cells to the NP(366)/D(b) variants.
CONCLUSIONS/SIGNIFICANCE: Pre-existing CD8 T cell immunity may provide substantial cross-protection against heterosubtypic influenza A viruses, provided that the priming and the subsequent challenge viruses share the identical sequences of the immunodominant, protective CTL epitopes.
在健康的人体中，广泛可检测到针对甲型流感病毒的记忆 CD8 T 细胞，且这些细胞对血清学上不同的甲型流感病毒亚型具有广泛的交叉反应性。然而，目前尚不清楚这种预先存在的细胞免疫在何种程度上能为新型甲型流感病毒提供交叉保护。
方法/主要发现：我们在小鼠模型中表明，病毒保守核蛋白的自然序列变异显著影响体内对致命疾病的交叉保护。当起始和挑战病毒具有相同的免疫显性保护性 NP(366)/D(b)表位序列时，观察到强烈的交叉保护。然而，当它们在这个表位上没有完全的序列同一性时，交叉保护大大降低。在这种情况下，病毒特异性抗体的贡献似乎微不足道。详细分析显示，由 NP(366)/D(b)变体引发的记忆 CD8 T 细胞反应的幅度明显低于由同源 NP(366)/D(b)配体引发的反应幅度。似乎是原始 NP(366)/D(b)配体的主导公共 TCR 对其严格的特异性限制了交叉反应性记忆 CD8 T 细胞对 NP(366)/D(b)变体的扩展。
结论/意义：预先存在的 CD8 T 细胞免疫可能为异源甲型流感病毒提供实质性的交叉保护，前提是起始和随后的挑战病毒具有免疫显性保护性 CTL 表位的相同序列。
