Induction of costimulation of human CD4 T cells by tumor necrosis factor–related apoptosis‐inducing ligand: Possible role in T cell activation in systemic lupus erythematosus

Abstract

Objective. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has recently been shown to induce costimulation of mouse T cells in conjunction with signals from the T cell receptor. This study was undertaken to investigate TRAIL-induced costimulation of human T cells in order to determine the role of TRAIL-induced T cell activation in human systemic lupus erythematosus (SLE).Methods. An in vitro T cell stimulation system with immobilized anti-CD3 and recombinant TRAIL receptor DR4-Fc proteins was used to activate human T cells purified from healthy individuals and from patients with SLE. The T cells were stimulated in vitro to assay their proliferation response by 3 H-thymidine incorporation, and their cytokine production by enzymelinked immunosorbent assay. Activation of p38 MAPK after TRAIL stimulation was detected with specific anti-phospho-p38 MAPK monoclonal antibodies in Western blots. Results. Enhanced T cell proliferation and increased interleukin-2 and interferon-␥ (IFN␥) production were demonstrated in human T cells after stimulation with immobilized DR4-Fc and anti-CD3 in vitro. TRAIL engagement selectively activated human CD4, rather than CD8, T cells and augmented IFN␥ production. Activation of p38 MAPK was detected after TRAILinduced T cell activation. T cells isolated from patientswith SLE demonstrated a stronger response to TRAILinduced costimulation, in terms of proliferation and increased up-regulation of CD25 after activation, when compared with T cells from healthy subjects.Conclusion. TRAIL engagement induces costimulation of human CD4 T cells via a p38 MAPKdependent pathway. The results suggest that enhanced reactivity of T cells to autoantigens as a result of TRAIL-induced costimulation may play a role in the development of human autoimmune diseases.

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

“…For example, our demonstration that TRAIL-defective donor CD4 ϩ T cells exhibit reduced proliferation and reduced numbers of effector/helper phenotype cells in chronic GVHD is consistent with data reported by Tsai et al (19) demonstrating that crosslinking of TRAIL by its receptors enhances anti-CD3-induced proliferation of CD4 ϩ T cells from either normal controls or lupus patients. However, Kaplan et al (29) have reported that TRAIL-positive T cells from lupus patients exhibit enhanced cytotoxic activity for autologous monocytes, which is mediated in part through up-regulated TRAIL, and through other molecules such as TNF-like weak inducer of apoptosis and FasL.…”

“…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).…”

Reduced Immunogenicity of First-Trimester Human Fetal Pancreas

“…In the present study, we also found a significant downregulation of several immune-related genes in the first-trimester fetal pancreas compared with second trimester, some identical to the genes demonstrated to be downregulated in the fetal kidneys, including MHC molecules, chemokines, complement components, and also TRAIL. These molecules are involved in recruiting T-cells and regulating their response (26,27), and TRAIL has been reported to have costimulatory activity on T-cells (28,29). The MHC class II molecules in particular are involved in triggering an immune response.…”

“…We also analyzed the expression of chemokine ligand 19 (CCL19) and complement component 3, because they are involved in recruiting T-cells and regulating their response (26,27), and the tumor necrosis factor (TNF) superfamily member 10 (TNFSF10 or TNF-related apoptosis-inducing ligand [TRAIL]), which has been reported to have costimulatory activity on T-cells (28,29). The upregulation of all of these genes in the second-trimester human fetal pancreas as seen in the microarray was confirmed by real-time RT-PCR.…”

Aberrant Phenotype and Function of Myeloid Dendritic Cells in Systemic Lupus Erythematosus

“…Indeed, individuals with SLE have autoreactive T cells that are specific for ubiquitous self-peptides and provide pathogenic B cell help (4,5). A pan T cell dysfunction in SLE is characterized by exaggerated CD4 ϩ T cell responses (6,7) and diminished CD8 ϩ T cell activities (8). Other alterations include changes in proliferative T cell responses as well as increased expression of early and late T cell activation markers (3, 7, 9 -11).…”