Death Ligand TRAIL Induces No Apoptosis but Inhibits Activation of Human (Auto)antigen-Specific T Cells

Abstract

TNF-related apoptosis-inducing ligand (TRAIL), a member of the TNF superfamily, induces apoptosis in susceptible cells, which can be both malignant and nontransformed. Despite homologies among the death ligands, there are great differences between the TRAIL system on the one hand and the TNF and CD95 systems on the other hand. In particular, TRAIL-induced apoptosis differs between rodents and man. Studies on animal models of autoimmune diseases suggested an influence of TRAIL on T cell growth and effector functions. Because we previously demonstrated that TRAIL does not induce apoptosis in human (auto)antigen-specific T cells, we now asked whether TRAIL exhibits other immunoregulatory properties in these cells. Active TRAIL inhibited calcium influx through store-operated calcium release-activated calcium channels, IFN-γ/IL-4 production, and proliferation. These effects were independent of APC, Ag specificity, and Th differentiation, and no differences were detected between healthy donors and multiple sclerosis patients. TRAIL affected neither the expression of the cell cycling inhibitor p27Kip1 nor the capacity of T cells to produce IL-2 upon Ag rechallenge, indicating that signaling via TRAIL receptor does not induce T cell anergy. Instead, the TRAIL-induced hypoproliferation could be attributed to the down-regulation of the cyclin-dependent kinase 4, indicating a G1 arrest of the cell cycle. Thus, although it does not contribute to mechanisms of peripheral T cell tolerance such as clonal anergy or deletion by apoptosis, TRAIL can directly inhibit activation of human T cells via blockade of calcium influx.

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

“…Our results demonstrating more robust proliferation of TRAIL KO CD8 ϩ T cells are supported by work in humans demonstrating that TRAIL decreases proliferation of Ag-specific T cell lines (17), particularly CD8 ϩ T cell blasts (57). Moreover, it has been shown recently that TRAIL is a key negative regulator of secondary CD8 ϩ T cell responses.…”

“…For example, in vitro data indicate that TRAIL can either suppress or costimulate T cell responses depending on whether it acts as a ligand or as a receptor, respectively (17)(18)(19). In vivo studies using TRAIL knockout (KO) mice or TRAIL blockade have demonstrated exacerbation of disease in murine models of collagen-induced arthritis (20), diabetes (21)(22)(23), and experimental autoimmune encephalomyelitis (24).…”

Human CD8+ T cell blasts are more sensitive than CD4+ T cell blasts to regulation by APO2L/TRAIL

“…Death receptor ligation on CD4 + or CD8 + T cell blasts induces, to different extents, cell cycle arrest in G 2 /M. A previous study described inhibition of growth in the absence of apoptosis induction by rApo2L on long-term autoreactive CD4 + T cell lines [35]. In that case, it was reported that rApo2L induced a decrease in CDK4 expression, and the authors concluded that, in consequence, rApo2L should induce cell cycle arrest at the G 1 /S transition.…”

TRAIL and immunity: more than a license to kill tumor cells

“…In line with this notion are previous reports showing that TRAIL inhibits DNA synthesis in human autoreactive T cells and prevents progression from G1 to S phase, without inducing apoptosis. 35 Apart from these direct effects of TRAIL on autoreactive T cells, TRAIL may regulate autoimmunity also at the level of antigen-presenting cells. As mentioned above, DC may become sensitive to TRAIL-induced apoptosis under certain conditions, and thus reduced antigen presentation will result in reduced T-cell activation and downregulation of the (auto-) immune response.…”