Keywords: Blood-brain barrier r CD4 + effector/memory T (T EM ) cells r Diapedesis r EAE r ICAM-1Additional supporting information may be found in the online version of this article at the publisher's web-site

2 Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF 3 superfamily that can lead to the induction of apoptosis in tumor or infected cells. However, activation 4 of TRAIL signaling may also trigger non-apoptotic pathways in cancer and in non-transformed cells, 5 i.e. immune cells. Here, we review the current knowledge on non-canonical TRAIL signaling. The 6 biological outcomes of TRAIL signaling in immune and malignant cells is presented and explained, 7 with a focus on the role of TRAIL for natural killer (NK) cell function. Furthermore, we highlight the 8 technical difficulties in dissecting the precise molecular mechanisms involved in the switch between 9 apoptotic and non-apoptotic TRAIL signaling. Finally, we discuss the consequences thereof for a 10 therapeutic manipulation of TRAIL in cancer and possible approaches to bypass these difficulties.

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 IFNc 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.