Inability of Plasmacytoid Dendritic Cells To Directly Lyse HIV-Infected Autologous CD4 ⁺ T Cells despite Induction of Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand

Abstract

The function of plasmacytoid dendritic cells (PDC) in chronic human immunodeficiency virus type 1 (HIV-1) infection remains controversial with regard to its potential for sustained alpha interferon (IFN-␣) production and induction of PDC-dependent tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-mediated cytotoxicity of HIV-infected cells. We address these areas by a study of chronically HIV-1-infected subjects followed through antiretroviral therapy (ART) interruption and by testing PDC cytolytic function against autologous HIV-infected CD4 ؉ T cells. Rebound in viremia induced by therapy interruption showed a positive association between TRAIL and viral load or T-cell activation, but comparable levels of plasma IFN-␣/␤ were found in viremic ART-treated and control subjects. While PDC from HIV-infected subjects expressed less interferon regulator factor 7 (IRF-7) and produced significantly less IFN-␣ upon Toll-like receptor 7/9 (TLR7/9) engagement than controls, membrane TRAIL expression in PDC from HIV ؉ subjects was increased. Moreover, no significant increase in death receptor 5 (DR5) expression was seen in CD4 ؉ T cells from viremic HIV ؉ subjects compared to controls or following in vitro infection/exposure to infectious and noninfectious virus or exogenous IFN-␣, respectively. Although activated PDC killed the DR5-expressing HIV-infected Sup-T1 cell line, PDC did not lyse primary autologous HIV ؉ CD4 ؉ T cells yet could provide accessory help for NK cells in killing HIV-infected autologous CD4 ؉ T cells. Taken together, our data show a lack of sustained high levels of soluble IFN-␣ in chronic HIV-1 infection in vivo and document a lack of direct PDC cytolytic activity against autologous infected or uninfected CD4 ؉ T cells.

Plasmacytoid Dendritic Cells Reduce HIV Production in Elite Controllers

“…A previous report demonstrated that the HIV stimulation of pDCs induces a high level of production of IFN-␣ and a rapid expression of TRAIL, transforming them into IFN-producing killer pDCs (iKpDCs) (5). It was also shown previously that despite TRAIL expression, pDCs could not induce the lysis of autologous CD4 ϩ T cells (1). However, in the present work, when primary HIV-infected autologous CD4 ϩ T cells were used as target cells, we also observed apoptosis induced by both unstimulated and TLR-9-stimulated pDCs.…”

TRAIL+ Human Plasmacytoid Dendritic Cells Kill Tumor Cells In Vitro: Mechanisms of Imiquimod- and IFN-α–Mediated Antitumor Reactivity

“…HIV, human T cell leukemia virus-1, and influenza virus, all natural ligands of TLR7, trigger a pDC innate immune response that not only involves the massive production of IFN-a, but also the upregulation of functionally active TRAIL (TRAIL/ Apo-2L/TNFSF10) (8)(9)(10). TRAIL is also expressed by HIVinfected pDCs (8,11,12), and, notably, TRAIL + pDCs may kill CD4 + T cells isolated from HIV-infected patients (12) and thus perhaps contribute to T cell depletion during HIV viremia. In addition to their role in viral immunity, several studies propose a direct role for cytotoxic pDCs in antitumor immunity.…”

Plasmacytoid Dendritic Cell Number and Responses to Toll-Like Receptor 7 and 9 Agonists Vary in HIV Type 1-Infected Individuals in Relation to Clinical State

“…15,[20][21][22] Induction of IFN-a by PDCs by various stimuli is directly related to the extent of down-regulation of the C-type lectin surface receptor BDCA-2 expressed on PDCs. 23 Thus, crosslinking or ligation of BDCA-2 with anti-BDCA-2 monoclonal antibodies (mAbs) has been reported to suppress IFN-a production by PDCs via TLR9 ligands such as HSV and CpGODNs [23][24][25][26] and to a much lesser extent via a TLR7 ligand such as influenza virus.…”