Cytomegalovirus-mediated expansion of IL-15-responsive innate-memory cells with SIV killing function

We investigated the effects of rhesus CMV (RhCMV) on composition and function of the immune system in young macaques. Within months of infection, RhCMV was associated with impressive changes in antigen presenting cells, T cells, and NK cells—and marked expansion of innate-memory CD8+ T cells. These cells express high levels of NKG2A/C and the IL-2- and IL-15-receptor beta chain, CD122. IL-15 was sufficient to drive differentiation of the cells in vitro and in vivo. Expanded NKG2A/C+CD122+CD8+ T cells in RhCMV-infected macaques, but not their NKG2-negative counterparts, were endowed with cytotoxicity against class I-deficient K562 targets and prompt IFN-? production in response to stimulation with IL-12 and IL-18. Because RhCMV clone 68-1 forms the viral backbone of RhCMV-vectored SIV vaccines, we also investigated immune changes following administration of RhCMV 68-1-vectored SIV vaccines. These vaccines led to impressive expansion of NKG2A/C+CD8+ T cells with capacity to inhibit SIV replication ex vivo. Thus, CMV infection and CMV-vectored vaccination drive expansion of functional innate-like CD8 cells via host IL-15 production, suggesting that innate-memory expansion could be achieved by other vaccine platforms expressing IL-15. Overall design: 6 RhCMV positive animals and 6 RhCMV negative animals were included in this study.

本研究探讨了恒河猴巨细胞病毒（rhesus CMV, RhCMV）对幼年猕猴免疫系统组成与功能的影响。感染后数月内，恒河猴巨细胞病毒与抗原呈递细胞、T细胞及自然杀伤细胞（NK cells）的显著改变相关，并伴随固有记忆CD8+ T细胞的明显扩增。该类细胞高表达NKG2A/C以及白细胞介素2、白细胞介素15受体β链CD122。白细胞介素15（IL-15）足以在体外及体内驱动该类细胞的分化。在恒河猴巨细胞病毒感染的猕猴体内扩增的NKG2A/C+CD122+CD8+ T细胞，而非其NKG2阴性的对应细胞，具备针对I类分子缺陷K562靶细胞的细胞毒性，并可在受到白细胞介素12（IL-12）与白细胞介素18（IL-18）刺激时快速产生干扰素γ（IFN-γ）。鉴于恒河猴巨细胞病毒克隆68-1是恒河猴巨细胞病毒载体猴免疫缺陷病毒（SIV）疫苗的病毒骨架，本研究同时探究了接种恒河猴巨细胞病毒68-1载体猴免疫缺陷病毒疫苗后的免疫变化。该类疫苗可显著扩增具备离体抑制猴免疫缺陷病毒复制能力的NKG2A/C+CD8+ T细胞。综上，巨细胞病毒感染及巨细胞病毒载体疫苗可通过宿主白细胞介素15的产生，驱动功能性固有样CD8+ T细胞的扩增，这提示表达白细胞介素15的其他疫苗平台亦可实现固有记忆T细胞的扩增。实验整体设计：本研究纳入6只恒河猴巨细胞病毒阳性动物与6只恒河猴巨细胞病毒阴性动物。