Holtappels Rafaela, Freitag Kirsten, Renzaho Angelique, Becker Sara, Lemmermann Niels A W, Reddehase Matthias J
Institute for Virology and Research Center for Immunotherapy (FZI) at the University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
Vaccines (Basel). 2020 Jul 22;8(3):402. doi: 10.3390/vaccines8030402.
Murine models of cytomegalovirus (CMV) infection have revealed an exceptional kinetics of the immune response. After resolution of productive infection, transient contraction of the viral epitope-specific CD8 T-cell pool was found to be followed by a pool expansion specific for certain viral epitopes during non-productive 'latent' infection. This phenomenon, known as 'memory inflation' (MI), was found to be based on inflationary KLRG1CD62L effector-memory T cells (iTEM) that depend on repetitive restimulation. MI gained substantial interest for employing CMV as vaccine vector by replacing MI-driving CMV epitopes with foreign epitopes for generating high numbers of protective memory cells specific for unrelated pathogens. The concept of an MI-driving CMV vector is questioned by human studies disputing MI in humans. A bias towards MI in experimental models may have resulted from systemic infection. We have here studied local murine CMV infection as a route that is more closely matching routine human vaccine application. Notably, KLRG1CD62L central memory T cells (TCM) and conventional KLRG1CD62L effector memory T cells (cTEM) were found to expand, associated with 'avidity maturation', whereas the pool size of iTEM steadily declined over time. The establishment of high avidity CD8 T-cell central memory encourages one to pursue the concept of CMV vector-based vaccines.
巨细胞病毒（CMV）感染的小鼠模型揭示了免疫反应的特殊动力学。在 productive 感染消退后，发现病毒表位特异性 CD8 T 细胞库短暂收缩，随后在非 productive“潜伏”感染期间，某些病毒表位特异性的细胞库出现扩增。这种现象被称为“记忆膨胀”（MI），发现其基于依赖重复再刺激的膨胀性 KLRG1CD62L 效应记忆 T 细胞（iTEM）。通过用外来表位取代驱动 MI 的 CMV 表位以产生大量针对无关病原体的保护性记忆细胞，MI 在将 CMV 用作疫苗载体方面引起了极大兴趣。人类研究对人类中的 MI 提出质疑，这对 MI 驱动的 CMV 载体概念提出了疑问。实验模型中对 MI 的偏向可能是由全身感染导致的。我们在此研究了局部小鼠 CMV 感染，这是一种与常规人类疫苗应用更紧密匹配的途径。值得注意的是，发现 KLRG1CD62L 中央记忆 T 细胞（TCM）和常规 KLRG1CD62L 效应记忆 T 细胞（cTEM）会扩增，并伴有“亲和力成熟”，而 iTEM 的细胞库大小随时间稳步下降。高亲和力 CD8 T 细胞中央记忆的建立鼓励人们探索基于 CMV 载体的疫苗概念。
