Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States.
Boston University School of Medicine, Boston, MA, United States.
Front Immunol. 2020 Jul 31;11:1676. doi: 10.3389/fimmu.2020.01676. eCollection 2020.
CD49a tissue resident NK cells have been implicated in memory-like NK cell responses, but while this population is well-characterized in mice and in humans, they are poorly described in non-human primates (NHP) which are particularly critical for modeling human viral infections. Others and we have shown that memory-like NK cells are enriched in the liver and because of the importance of NHP in modeling HIV infection, understanding the immunobiology of CD49a NK cells in SIV-infected rhesus macaques is critical to explore the role of this cell type in retroviral infections. In this study mononuclear cells isolated from livers, spleens, and peripheral whole blood were analyzed in acutely and chronically lentivirus-infected and experimentally-naïve Indian rhesus macaques (RM). NK cells were then identified as CD45CD14CD20CD3NKG2A/C cells and characterized using multiparametric flow-cytometry. Our data show that in RM, CD49a NK cells increase in the liver following retroviral infections [median = 5.2% (naïve) vs. median = 9.48% (SIV+) or median = 16.8% (SHIV+)]. In contrast, there is little change in CD49a NK frequencies in whole blood or spleens of matched animals. In agreement with human and murine data we also observed that CD49a NK cells were predominantly Eomes T-bet, though these frequencies are elevated in infected animal cohorts. Functionally, our data suggests that infection alters TNF-α, IFN-γ, and CD107a expression in stimulated CD49a NK cells. Specifically, our analyses found a decrease in CD49a CD107a TNFα IFNγ NK cells, with a simultaneous increase in CD49a CD107a TNFα IFNγ NK cells and the non-responsive CD49a CD107a TNFα IFNγ NK cell population following infection, suggesting both pathogenic and inflammatory changes in the NK cell functional profile. Our data also identified significant global differences in polyfunctionality between CD49a NK cells in the naïve and chronic (SHIV+) cohorts. Our work provides the first characterization of CD49a NK cells in tissues from RM. The significant similarities between CD49a NK cells from RM and what is reported from human samples justifies the importance of studying CD49a NK cells in this species to support preclinical animal model research.
CD49a 组织驻留 NK 细胞被认为与记忆样 NK 细胞反应有关，但尽管这种细胞在小鼠和人类中得到了很好的描述，但在非人类灵长类动物（NHP）中描述得很差，而 NHP 对于模拟人类病毒感染尤为关键。其他人（包括我们）已经表明，记忆样 NK 细胞在肝脏中富集，由于 NHP 在模拟 HIV 感染中的重要性，因此研究 SIV 感染恒河猴中 CD49a NK 细胞的免疫生物学对于探索这种细胞类型在逆转录病毒感染中的作用至关重要。在这项研究中，从急性和慢性慢病毒感染及实验性未感染的印度恒河猴（RM）的肝脏、脾脏和外周全血中分离出单核细胞，并进行分析。然后，通过多参数流式细胞术鉴定 NK 细胞为 CD45CD14CD20CD3NKG2A/C 细胞，并对其进行特征描述。我们的数据表明，在 RM 中，逆转录病毒感染后，肝脏中的 CD49a NK 细胞增加[中位数=5.2%（未感染）vs. 中位数=9.48%（SIV+）或中位数=16.8%（SHIV+）]。相比之下，在匹配动物的全血或脾脏中，CD49a NK 细胞的频率几乎没有变化。与人类和小鼠数据一致，我们还观察到 CD49a NK 细胞主要为 Eomes T-bet，但在感染动物队列中这些频率升高。功能上，我们的数据表明，感染改变了刺激的 CD49a NK 细胞中 TNF-α、IFN-γ 和 CD107a 的表达。具体来说，我们的分析发现，感染后 CD49a CD107a TNFα IFNγ NK 细胞减少，同时 CD49a CD107a TNFα IFNγ NK 细胞和无反应性 CD49a CD107a TNFα IFNγ NK 细胞群增加，表明 NK 细胞功能谱中存在致病和炎症变化。我们的数据还表明，在未感染和慢性（SHIV+）队列的 CD49a NK 细胞之间，多效性功能存在显著的整体差异。我们的工作首次描述了 RM 组织中 CD49a NK 细胞的特征。CD49a NK 细胞在 RM 和人类样本中的报告之间存在显著相似性，这证明了在该物种中研究 CD49a NK 细胞的重要性，以支持临床前动物模型研究。
