Department of Pathology, University of Massachusetts Chan Medical School, Worcester, MA, United States.
Front Immunol. 2023 Dec 12;14:1306433. doi: 10.3389/fimmu.2023.1306433. eCollection 2023.
Our recent studies reveal that the persistence, location, and amount of both antigen and signals that induce pathogen recognition responses determine the number of CD4 memory cells, the subsets that develop, their location, and hence their protective efficacy. Non-replicating vaccines provide antigen that is short-lived and generate low levels of only some memory subsets that are mostly restricted to secondary lymphoid tissue. In contrast, exposure to long-lived replicating viruses and bacteria provides high levels of diverse antigens in sites of infection and induces strong pathogen recognition signals for extended periods of time, resulting in much higher levels of memory cells of diverse subsets in both lymphoid and nonlymphoid sites. These include memory subsets with highly potent functions such as T follicular helpers and cytotoxic CD4 effectors at sites of infection, where they can most effectively combat the pathogen early after re-infection. These effectors also do not develop without antigen and pathogen recognition signals at the effector stage, and both subsets must receive these signals in the tissue sites where they will become resident. We postulate that this leads to a hierarchical structure of memory, with the strongest memory induced only by replicating pathogens. This paradigm suggests a likely roadmap for markedly improving vaccine design.
我们最近的研究表明，抗原的持久性、位置和数量以及诱导病原体识别反应的信号决定了 CD4 记忆细胞的数量、发育的亚群、它们的位置，从而决定了它们的保护效果。非复制疫苗提供的抗原寿命短，只能产生一些主要局限于次级淋巴组织的记忆亚群的低水平。相比之下，暴露于长期复制的病毒和细菌会在感染部位提供高水平的多样化抗原，并诱导长时间的强烈病原体识别信号，从而在淋巴和非淋巴部位产生更高水平的多样化记忆细胞亚群。这些记忆亚群包括在感染部位具有高度有效功能的 T 滤泡辅助细胞和细胞毒性 CD4 效应细胞，它们可以在再次感染后早期最有效地对抗病原体。这些效应细胞也不会在效应阶段没有抗原和病原体识别信号的情况下发育，并且这两个亚群都必须在它们将成为常驻的组织部位接收这些信号。我们假设，这导致了记忆的层次结构，只有复制的病原体才能诱导最强的记忆。这一范例为显著改善疫苗设计提供了一个可能的路线图。
