title: TRAIL-receptor costimulation inhibits proximal TCR signaling and suppresses human T cell activation and proliferation.
abstract: The TRAIL-receptor/TRAIL system originally described to induce apoptosis preferentially in malignant cells is also known to be involved in T cell homeostasis and the response to viral infections and autoimmune diseases. Whereas the expression of TRAIL on activated NK and T cells increases their cytotoxicity, induction of TRAIL on APCs can turn them into apoptosis inducers but might also change their immunostimulatory capacity. Therefore, we analyzed how TRAIL-receptor (TRAIL-R) costimulation is modulating TCR-mediated activation of human T cells. T cells triggered by rTRAIL in combination with anti-CD3 and -CD28 Abs exhibited a strong decrease in the expression of activation markers and Th1 and Th2 cytokines compared with CD3/CD28-activated T cells. Most importantly, proliferation of TRAIL-R costimulated T cells was strongly impaired, but no apoptosis was induced. Addition of exogenous IL-2 could not rescue T cells silenced by TRAIL-R costimulation, and TRAIL-mediated inhibition of T cell proliferation only prevented TCR-triggered proliferation but was ineffective if T cells were activated downstream of the TCR. Inhibition of T cell proliferation was associated with abrogation of proximal TCR signaling by inhibiting recruitment of TCR-associated signaling molecules to lipid rafts, followed by abrogation of protein tyrosine phosphorylation of ZAP70, phospholipase C-γ1, and protein kinase C-θ, and impaired nuclear translocation of NFAT, AP-1, and NF-κB. Most importantly, TRAIL-R costimulation efficiently inhibited alloantigen-induced T cell proliferation and CD3/28-induced activation and proliferation of autoreactive T cells derived from patients with Omenn syndrome, indicating that coactivation of TRAIL-R and TCR represents a mechanism to downmodulate T cell immune responses.
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, 89075 Ulm, Germany;
authors.forename: Corinna
authors.initials: C
authors.lastname: Lehnert
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, 89075 Ulm, Germany;
authors.forename: Maxi
authors.initials: M
authors.lastname: Weiswange
authors.affiliation: Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 Munich, Germany; and.
authors.forename: Irmela
authors.initials: I
authors.lastname: Jeremias
authors.affiliation: University Medical Center Ulm, Institute of Virology, 89081 Ulm, Germany.
authors.forename: Carina
authors.initials: C
authors.lastname: Bayer
authors.affiliation: Helmholtz Zentrum München, German Research Center for Environmental Health, 81377 Munich, Germany; and.
authors.forename: Michaela
authors.initials: M
authors.lastname: Grunert
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, 89075 Ulm, Germany;
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Debatin
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, 89075 Ulm, Germany; gudrun.strauss@uniklinik-ulm.de.
authors.forename: Gudrun
authors.initials: G
authors.lastname: Strauss
mesh_terms: D021581:Active Transport, Cell Nucleus; D017209:Apoptosis / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D006801:Humans; D007376:Interleukin-2 / Q000096:biosynthesis; D007527:Isoenzymes / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D021962:Membrane Microdomains / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D000074121:Protein Kinase C-theta; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology*; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D018808:Transcription Factor AP-1 / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase / Q000378:metabolism
chemical_list: D018106:CD28 Antigens; D017252:CD3 Complex; C508594:IL2 protein, human; D007376:Interleukin-2; D007527:Isoenzymes; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D011948:Receptors, Antigen, T-Cell; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D018808:Transcription Factor AP-1; D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; C076233:PRKCQ protein, human; D011493:Protein Kinase C; D000074121:Protein Kinase C-theta; C522157:PLCG1 protein, human; D051966:Phospholipase C gamma