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Non-apoptotic TRAIL function modulates NK cell activity during viral infection
- Journal Article
The role of death receptor signaling for pathogen control and infection-associated pathogenesis is multifaceted and controversial. Here, we show that during viral infection, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) modulates NK cell activity independently of its pro-apoptotic function. In mice infected with lymphocytic choriomeningitis virus (LCMV), Trail deficiency led to improved specific CD8(+) T-cell responses, resulting in faster pathogen clearance and reduced liver pathology. Depletion experiments indicated that this effect was mediated by NK cells. Mechanistically, TRAIL expressed by immune cells positively and dose-dependently modulates IL-15 signaling-induced granzyme B production in NK cells, leading to enhanced NK cell-mediated T cell killing. TRAIL also regulates the signaling downstream of IL-15 receptor in human NK cells. In addition, TRAIL restricts NK1.1-triggered IFN gamma production by NK cells. Our study reveals a hitherto unappreciated immunoregulatory role of TRAIL signaling on NK cells for the granzyme B-dependent elimination of antiviral T cells. Synopsis xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="urn:x-wiley:1469221X:embr201948789:embr201948789-abs-0001 TRAIL modulates NK cell function by repressing NK1.1-triggered IFN gamma production. TRAIL also promotes IL-15 signaling-dependent granzyme B expression in NK cells, thereby supporting NK cell-mediated T-cell killing during virus infection. TRAIL modulates NK cells by repressing IFN gamma production and promoting IL-15-dependent granzyme B expression. Membrane-bound TRAIL activates TRAIL/TRAIL receptor signaling, which regulates the IL-15-granzyme B axis. TRAIL-dependent granzyme B expression improves NK cell-mediated restriction of antiviral CD8(+) T-cell responses. Enhanced granzyme B expression in NK cells is associated with impaired LCMV clearance. Show more
Journal / seriesEMBO Reports
SubjectCD8 T cells; IL-15 signaling; lymphocytic choriomeningitis virus; NK cells; TNF-related apoptosis-inducing ligand
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