Regulation of TNF-related apoptosis-inducing ligand on primary CD4 ⁺ T cells by HIV-1: Role of type I IFN-producing plasmacytoid dendritic cells

Abstract

TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, was suggested to contribute to HIV-1 pathogenesis by inducing CD4 ؉ T cell death characteristic of AIDS. We previously reported HIV-1-mediated, TRAIL-induced apoptosis in primary CD4 ؉ T cells in vitro and observed elevated levels of plasma TRAIL in HIV-1-infected patients. The present study elucidates the unresolved mechanism by which HIV-1 induces TRAIL expression on primary CD4 ؉ T cells. We demonstrate that the expression of TRAIL by primary CD4 ؉ T cells is regulated by IFN-␣ that is produced by HIV-1-stimulated plasmacytoid dendritic cells (pDCs). We also found that IFN-induced TRAIL is mediated by signal transducers and activators of transcription 1 and 2. We show that IFN-␣ production by HIV-1-activated pDCs is blocked by an early viral entry inhibitor of CD4-gp120 binding, but not by inhibitors of viral coreceptor binding. Our in vitro data are supported by the demonstration that anti-IFN-␣ and -␤ Abs inhibit apoptosis and TRAIL expression in CD4 ؉ T cells from HIV-1-infected patients. Our findings suggest a potential unique role of pDCs in the immunopathogenesis of HIV-1 infection by inducing the death molecule TRAIL.T NF-related apoptosis-inducing ligand (TRAIL), a TNF superfamily member (1), has two death receptors (DRs) that induce apoptosis (2) (DR4 and DR5) and three other receptors that lack the death domain and engage ligand without initiating apoptosis (3). TRAIL protein is expressed on the cell membrane (mTRAIL) or is secreted (soluble TRAIL) (1), and both the soluble and membrane-bound forms induce apoptosis of cells expressing functional DRs (4). TRAIL may contribute to HIV-1 immunopathogenesis because CD4 ϩ and CD8 ϩ T cells from HIV-1-infected patients are more susceptible to TRAILinduced apoptosis in vitro than T cells from healthy donors (5-7). TRAIL induced the selective apoptosis of uninfected CD4 ϩ T cells in HIV-1-infected hu-PBL-NOD-SCID mice (8). TRAIL, produced by monocytes exposed to the HIV-1 Tat protein, induced apoptosis of uninfected CD4 ϩ T cells (9). We recently reported that plasma TRAIL levels in HIV-1-infected patients directly correlate with viral load (10). We also reported that CD4 ϩ T cells exposed to HIV-1 underwent apoptosis by a TRAIL-DR5-dependent mechanism, which was inhibited by anti-type I IFN Abs (11). These latter results suggest that type I IFN plays a fundamental role in HIV-1-induced TRAIL expression by CD4 ϩ T cells.Type I IFN (IFN-␣͞␤) has antiviral activity, including activity against HIV-1 (12). IFN-␣͞␤ are produced mainly by plasmacytoid dendritic cells (pDCs) (13). pDCs are located in blood and lymphoid tissue (13-15) and participate in innate immune responses against viruses by producing large amounts of 17). Interestingly, pDCs secrete type I IFN when stimulated by infectious HIV-1 or chemically inactivated HIV-1 virions (18). The majority of plasma HIV-1 is not infectious (19,20), raising the possibility that such virions contribute to HIV-1 pathogenesis and CD4 ϩ T c...

The Calcineurin B Subunit (CnB) Is a New Ligand of Integrin αM That Mediates CnB-Induced Apo2L/TRAIL Expression in Macrophages

“…TRAIL induces apoptosis of a variety of tumor cells while displaying no cytotoxicity against most normal cells; this makes it a promising new agent for cancer therapy. It has been reported that in immune cells, TRAIL is induced mainly by the type I or II IFN-mediated JAK/STAT (37)(38)(39)(40) and TLR agonist-mediated TLR pathways (41)(42)(43). To our knowledge, this is the first report that TRAIL expression is mediated by integrin aM, and our findings should add to understanding of the mechanisms regulating TRAIL expression.…”

“…It is expressed on activated T cells, NK cells, macrophages, monocytes, dendritic cells, and neutrophils and plays important roles in tumor surveillance and defense against viral infections and many other physiological and pathological processes (35,36). In immune cells, TRAIL is induced by several pathways including the type I or II IFN-mediated JAK/STAT (37)(38)(39)(40) and TLR agonist-mediated TLR pathways (41)(42)(43). Histone deacetylase inhibitors induce TRAIL in human breast tumors via the transcription factor Sp1 (44), and proline oxidase promotes TRAIL expression via NFAT (45).…”

IFN-α Exerts Opposing Effects on Activation-Induced and IL-7–Induced Proliferation of T Cells That May Impair Homeostatic Maintenance of CD4+ T Cell Numbers in Treated HIV Infection

“…In addition, other factors may contribute to persistent CD4 + T cell depletion, including an increased propensity of CD4 + T cells to undergo apoptosis mediated by molecules of the TNF family, such as TRAIL (23,40) and TNF-a, which has been linked with CD4 + T cell depletion in a study of patients with a defined resumption of HIV replication after cessation of ART (52). Indeed, there is evidence that IFN-a contributes to the increased sensitivity of CD4 + T cells to apoptosis in HIV patients (23,53).…”

T Cell TRAIL Promotes Murine Lupus by Sustaining Effector CD4 Th Cell Numbers and by Inhibiting CD8 CTL Activity

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