Xu Xuequn, Petersen Sean, Rodriguez Cynthia, Yi Guohua
Center of Emphasis in Infectious Diseases, Department of Biomedical Sciences, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, United States.
Department of Pulmonary Immunology, The University of Texas Health Science Center at Tyler, United States.
Heliyon. 2021 Jul 8;7(7):e07496. doi: 10.1016/j.heliyon.2021.e07496. eCollection 2021 Jul.
Phagocytosis is a critical component of the innate immune response to viral infection, resulting in the clearance of infected cells while minimizing the exposure of uninfected cells. On the other hand, phagocytosis of HIV-infected T cells may cause phagocytes, such as macrophages and dendritic cells, to be infected, thus leading to HIV cell-to-cell transmission. V domain immunoglobulin suppressor of T cell activation (VISTA, gene Vsir, aliases Gi24, Dies-1, PD-1H, and DD1α) has been identified as an immune checkpoint molecule that possesses dual activities when expressed on APCs and T cells. Our study found that VISTA might play a significant role during the immune response to HIV infection via apoptosis upregulation and subsequent phagocytosis of infected CEM-SS T cells. HIV-induced apoptosis and monocytic cell engulfment were tested utilizing CEM-SS T cells as target cells and the monocytic cell line THP-1 as phagocytic cells. Cells were infected with a GFP-labeled HIV strain, NL4-3. HIV-infected CEM-SS T cells displayed greater apoptotic activity (approximately 18.0%) than mock-infected controls. Additionally, phagocytosis of HIV-infected CEM-SS T cells was increased approximately 4-fold. Expression of VISTA on infected CEM-SS T cells was detected in 16.7% of cells, which correlated with the increased phagocytosis observed. When an antagonistic antibody against VISTA was used, the number of phagocytosed cells was reduced by a factor of 2, which was replicated utilizing human stem cell-derived dendritic cells. Phagocytosis was also confirmed by the upregulation of IL-1β expression, which was 5-fold higher in infected cells than in control cells. We also found that VISTA overexpression on both phagocytes and HIV-infected CEM-SS T cells facilitated phagocytosis. Our study suggests that VISTA may act as a direct ligand in the phagocytosis of HIV-infected T cells.
吞噬作用是对病毒感染的固有免疫反应的关键组成部分，可清除被感染细胞，同时尽量减少未感染细胞的暴露。另一方面，HIV感染的T细胞的吞噬作用可能导致吞噬细胞（如巨噬细胞和树突状细胞）被感染，从而导致HIV细胞间传播。T细胞激活的V结构域免疫球蛋白抑制剂（VISTA，基因Vsir，别名Gi24、Dies-1、PD-1H和DD1α）已被鉴定为一种免疫检查点分子，当在抗原呈递细胞（APC）和T细胞上表达时具有双重活性。我们的研究发现，VISTA可能通过上调凋亡以及随后对被感染的CEM-SS T细胞的吞噬作用，在对HIV感染的免疫反应中发挥重要作用。利用CEM-SS T细胞作为靶细胞，单核细胞系THP-1作为吞噬细胞，检测HIV诱导的凋亡和单核细胞吞噬。细胞用绿色荧光蛋白（GFP）标记的HIV毒株NL4-3感染。与模拟感染的对照相比，HIV感染的CEM-SS T细胞表现出更高的凋亡活性（约18.0%）。此外，HIV感染的CEM-SS T细胞的吞噬作用增加了约4倍。在16.7%的细胞中检测到被感染的CEM-SS T细胞上VISTA的表达，这与观察到的吞噬作用增加相关。当使用抗VISTA的拮抗抗体时，吞噬细胞的数量减少了一半，利用人干细胞衍生的树突状细胞也得到了同样的结果。IL-1β表达上调也证实了吞噬作用，感染细胞中的IL-1β表达比对照细胞高5倍。我们还发现，吞噬细胞和HIV感染的CEM-SS T细胞上VISTA的过表达促进了吞噬作用。我们的研究表明，VISTA可能在HIV感染的T细胞的吞噬作用中充当直接配体。
