Rapid Influx and Death of Plasmacytoid Dendritic Cells in Lymph Nodes Mediate Depletion in Acute Simian Immunodeficiency Virus Infection

被引:106
作者
Brown, Kevin N. [1 ,2 ]
Wijewardana, Viskam [2 ]
Liu, Xiangdong [2 ]
Barratt-Boyes, Simon M. [1 ,2 ]
机构
[1] Univ Pittsburgh, Grad Sch Publ Hlth, Dept Infect Dis & Microbiol, Pittsburgh, PA 15261 USA
[2] Univ Pittsburgh, Sch Med, Ctr Vaccine Res, Pittsburgh, PA 15261 USA
基金
美国国家卫生研究院;
关键词
ANTIGEN-PRESENTING CELLS; I INTERFERON-PRODUCTION; CD4(+) T-CELLS; ACTIVE ANTIRETROVIRAL THERAPY; PRIMARY HIV-1 INFECTION; TYPE-1; INFECTION; BONE-MARROW; RHESUS MACAQUES; SIV INFECTION; CYNOMOLGUS MACAQUES;
D O I
10.1371/journal.ppat.1000413
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Plasmacytoid dendritic cells (pDC) are essential innate immune system cells that are lost from the circulation in human immunodeficiency virus (HIV)-infected individuals associated with CD4(+) T cell decline and disease progression. pDC depletion is thought to be caused by migration to tissues or cell death, although few studies have addressed this directly. We used precise methods of enumeration and in vivo labeling with 5-bromo-2'-deoxyuridine to track recently divided pDC in blood and tissue compartments of monkeys with acute pathogenic simian immunodeficiency virus (SIV) infection. We show that pDC are lost from blood and peripheral lymph nodes within 14 days of infection, despite a normal frequency of pDC in bone marrow. Paradoxically, pDC loss masked a highly dynamic response characterized by rapid pDC mobilization into blood and a 10- to 20-fold increase in recruitment to lymph nodes relative to uninfected animals. Within lymph nodes, pDC had increased levels of apoptosis and necrosis, were uniformly activated, and were infected at frequencies similar to CD4(+) T cells. Nevertheless, remaining pDC had essentially normal functional responses to stimulation through Toll-like receptor 7, with half of lymph node pDC producing both TNF-alpha and IFN-alpha. These findings reveal that cell migration and death both contribute to pDC depletion in acute SIV infection. We propose that the rapid recruitment of pDC to inflamed lymph nodes in lentivirus infection has a pathologic consequence, bringing cells into close contact with virus, virus-infected cells, and pro-apoptotic factors leading to pDC death.
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页数:13
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