Influence of Plasma Cell Niche Factors on the Recruitment and Maintenance of IRF4hi Plasma Cells and Plasmablasts in Vaccinated, Simian Immunodeficiency Virus-Infected Rhesus Macaques with Low and High Viremia.
Influence of Plasma Cell Niche Factors on the Recruitment and Maintenance of IRF4hi Plasma Cells and Plasmablasts in Vaccinated, Simian Immunodeficiency Virus-Infected Rhesus Macaques with Low and High Viremia.
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浆细胞生态位因子对免疫、猿猴免疫缺陷病毒感染、低病毒血症和高病毒血症的恒河猴中 IRF4hi 浆细胞和浆母细胞的招募和维持的影响。
DOI：
10.1128/jvi.01727-16
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发表时间：
2017
影响因子：
5.4
通讯作者：
Robert-Guroff,Marjorie
中科院分区：
文献类型：
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作者：
Shaw,JuliaM;Miller-Novak,LeiaK;Mohanram,Venkatramanan;McKinnon,Katherine;Demberg,Thorsten;Vargas-Inchaustegui,DiegoA;Venzon,David;Robert-Guroff,Marjorie
在最近的一项研究中，我们发现，在接种疫苗的雌性恒河猴中，接触猿猴免疫缺陷病毒（SIV）后的保护作用与直肠浆细胞频率相关。我们试图确定相同的猕猴在感染后是否保持高粘膜浆细胞频率，以及这是否会导致病毒血症减少。尽管延迟获得 SIV 并不能预测随后的病毒控制，但表现出高或低病毒血症的猕猴之间浆细胞和浆母细胞的分布存在变化。对来自已接种疫苗的感染者、未接种疫苗的感染者和未感染的猕猴的直肠活检标本、骨髓和肠系膜淋巴结的细胞进行流式细胞术分析，确定了两个主要的IRF4hi亚群：CD138+浆细胞和CD138-浆母细胞。在直肠组织中，浆细胞频率与血浆病毒血症呈正相关，与接种疫苗的动物相比，未接种疫苗的猕猴的浆细胞和浆母细胞增加。同样，肠系膜淋巴结中的浆母细胞频率与病毒血症相关。然而，在骨髓中，浆母细胞频率与病毒血症呈负相关。因此，低病毒血症的猕猴比高病毒血症的动物具有更高的骨髓 IRF4hi 亚群频率。直肠和骨髓浆母细胞之间的显着相互关系表明，有效运输到骨髓而不是直肠粘膜与病毒控制有关。对分选的骨髓和直肠细胞群中浆细胞微环境建立所涉及的蛋白质的 mRNA 表达分析进一步支持了该模型，并揭示了这些组织中差异的 mRNA 表达模式。 重要性 作为关键的抗体生产者，浆细胞和浆母细胞是疫苗诱导的人体免疫缺陷病毒 1 型 (HIV-1) 和猕猴模型中的 SIV 免疫的关键组成部分；然而，很少有人尝试检查这些细胞在感染后病毒抑制中的作用。我们的结果表明，浆母细胞运输和保留在骨髓中在病毒控制中发挥着以前未被认识到的作用，并将粘膜浆细胞在介导感染部位保护的潜在贡献与骨髓浆母细胞和浆细胞在慢性感染期间控制病毒血症的潜在贡献进行了对比。影响这些关键抗体分泌细胞的分布和维持的利基因素的操纵可以作为潜在的治疗靶点，以增强疫苗接种后和感染后的抗病毒反应。
In a recent study, we found that protection following simian immunodeficiency virus (SIV) exposure correlated with rectal plasma cell frequency in vaccinated female rhesus macaques. We sought to determine if the same macaques maintained high mucosal plasma cell frequencies postinfection and if this translated to reduced viremia. Although delayed SIV acquisition did not predict subsequent viral control, alterations existed in the distribution of plasma cells and plasmablasts between macaques that exhibited high or low viremia. Flow cytometric analysis of cells from rectal biopsy specimens, bone marrow, and mesenteric lymph nodes of vaccinated infected, unvaccinated infected, and uninfected macaques identified two main IRF4hisubsets of interest: CD138+plasma cells, and CD138−plasmablasts. In rectal tissue, plasma cell frequency positively correlated with plasma viremia and unvaccinated macaques had increased plasma cells and plasmablasts compared to vaccinated animals. Likewise, plasmablast frequency in the mesenteric lymph node correlated with viremia. However, in bone marrow, plasmablast frequency negatively correlated with viremia. Accordingly, low-viremic macaques had a higher frequency of both bone marrow IRF4hisubsets than did animals with high viremia. Significant reciprocal relationships between rectal and bone marrow plasmablasts suggested that efficient trafficking to the bone marrow as opposed to the rectal mucosa was linked to viral control. mRNA expression analysis of proteins involved in establishment of plasma cell niches in sorted bone marrow and rectal cell populations further supported this model and revealed differential mRNA expression patterns in these tissues.IMPORTANCEAs key antibody producers, plasma cells and plasmablasts are critical components of vaccine-induced immunity to human immunodeficiency virus type 1 (HIV-1) in humans and SIV in the macaque model; however, few have attempted to examine the role of these cells in viral suppression postinfection. Our results suggest that plasmablast trafficking to and retention in the bone marrow play a previously unappreciated role in viral control and contrast the potential contribution of mucosal plasma cells to mediate protection at sites of infection with that of bone marrow plasmablasts and plasma cells to control viremia during chronic infection. Manipulation of niche factors influencing the distribution and maintenance of these critical antibody-secreting cells may serve as potential therapeutic targets to enhance antiviral responses postvaccination and postinfection.