Berenzon Dmitri, Schwenk Robert J, Letellier Lisa, Guebre-Xabier Mimi, Williams Jackie, Krzych Urszula
Department of Immunology and Entomology, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
J Immunol. 2003 Aug 15;171(4):2024-34. doi: 10.4049/jimmunol.171.4.2024.
We previously demonstrated that protection induced by radiation-attenuated (gamma) Plasmodium berghei sporozoites is linked to MHC class I-restricted CD8(+) T cells specific for exoerythrocytic-stage Ags, and that activated intrahepatic memory CD8(+) T cells are associated with protracted protection. In this study, we further investigated intrahepatic memory CD8(+) T cells to elucidate mechanisms required for their maintenance. Using phenotypic markers indicative of activation (CD44, CD45RB), migration (CD62L), and IFN-gamma production, we identified two subsets of intrahepatic memory CD8(+) T cells: the CD44(high)CD45RB(low)CD62L(low)CD122(low) phenotype, representing the dominant effector memory set, and the CD44(high)CD45RB(high)CD62L(low/high)CD122(high) phenotype, representing the central memory set. Only the effector memory CD8(+) T cells responded swiftly to sporozoite challenge by producing sustained IFN-gamma; the central memory T cells responded with delay, and the IFN-gamma reactivity was short-lived. In addition, the subsets of liver memory CD8(+) T cells segregated according to the expression of CD122 (IL-15R) in that only the central memory CD8(+) T cells were CD122(high), whereas the effector memory CD8(+) T cells were CD122(low). Moreover, the effector memory CD8(+) T cells declined as protection waned in mice treated with primaquine, a drug that interferes with the formation of liver-stage Ags. We propose that protracted protection induced by P. berghei radiation-attenuated sporozoites depends in part on a network of interactive liver memory CD8(+) T cell subsets, each representing a different phase of activation or differentiation, and the balance of which is profoundly affected by the repository of liver-stage Ag and IL-15.
我们先前证明，辐射减毒（γ）伯氏疟原虫子孢子诱导的保护作用与针对红细胞外期抗原的MHC I类限制性CD8⁺ T细胞有关，并且活化的肝内记忆CD8⁺ T细胞与持久保护相关。在本研究中，我们进一步研究肝内记忆CD8⁺ T细胞，以阐明其维持所需的机制。使用指示活化（CD44、CD45RB）、迁移（CD62L）和IFN-γ产生的表型标志物，我们鉴定出肝内记忆CD8⁺ T细胞的两个亚群：CD44高CD45RB低CD62L低CD122低表型，代表主要的效应记忆组；以及CD44高CD45RB高CD62L低/高CD122高表型，代表中央记忆组。只有效应记忆CD8⁺ T细胞通过产生持续的IFN-γ对子孢子攻击迅速作出反应；中央记忆T细胞反应延迟，且IFN-γ反应性短暂。此外，肝记忆CD8⁺ T细胞亚群根据CD122（IL-15R）的表达而分离，即只有中央记忆CD8⁺ T细胞是CD122高，而效应记忆CD8⁺ T细胞是CD122低。此外，在用干扰肝期抗原形成的药物伯氨喹治疗的小鼠中，随着保护作用减弱，效应记忆CD8⁺ T细胞减少。我们提出，伯氏疟原虫辐射减毒子孢子诱导的持久保护部分取决于相互作用的肝记忆CD8⁺ T细胞亚群网络，每个亚群代表激活或分化的不同阶段，其平衡受到肝期抗原库和IL-15的深刻影响。
