Abstract
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-α and IFN-α. 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.
Highlights
Plasmacytoid dendritic cells are important in bridging innate and adaptive immune responses to pathogens [1,2,3]. pDC derive from bone marrow and are recruited into lymph nodes in response to inflammation, producing type I interferon (IFN) and contributing to the generation of virus-specific T cell responses [2,3,4,5]
We found that pDC were present in normal numbers in bone marrow but were lost from blood and lymph nodes within 14 days of intravenous infection
We conclude that migration and death both contribute to pDC depletion, with influx into lymph nodes bringing cells into an environment favoring their death by infection or apoptosis
Summary
Plasmacytoid dendritic cells (pDC) are important in bridging innate and adaptive immune responses to pathogens [1,2,3]. pDC derive from bone marrow and are recruited into lymph nodes in response to inflammation, producing type I interferon (IFN) and contributing to the generation of virus-specific T cell responses [2,3,4,5]. A central hypothesis accounting for pDC depletion from blood during HIV infection is recruitment to inflamed lymphoid tissues [18,21]. Evidence for pDC recruitment comes from the finding that pDC exposed to HIV express the chemokine receptor CCR7 required for homing to lymph node paracortex [21], and recent data in rhesus macaques confirm that CCR7 is induced on circulating pDC in response to pathogenic SIV infection [22]. There is substantial evidence to support a role for cell death in pDC loss in HIV infection. PDC from HIV-infected individuals undergo death by apoptosis and necrosis following interaction and fusion with HIVinfected cells [17]. The relative contribution of recruitment to tissues and cell death to pDC loss in HIV infection remains to be determined
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