title: ICOS-LICOS interaction is critically involved in TGN1412-mediated T-cell activation.
abstract: TGN1412, a superagonistic CD28-specific antibody, was shown to require Fc-cross-linking or immobilization as a prerequisite to mediate T-cell proliferation and cytokine release in vitro. We used primary human umbilical vein endothelial cells (HUVECs) to study their ability to induce activation of TGN1412-treated T cells. We confirmed that peripheral primary human T cells do not show activation upon stimulation with soluble TGN1412 alone. Nevertheless, cocultivation of TGN1412-treated T cells with HUVECs induced T-cell activation that was further enhanced using cytokine prestimulated HUVECs. Unexpectedly, Fc-FcγR interaction was dispensable for endothelial cell-mediated proliferation of TGN1412-treated T cells. Transwell-culture assays showed that TGN1412-treated T cells need direct cell-to-cell contact to HUVECs to induce proliferation. We found that costimulatory ICOS-LICOS interaction between T cells and endothelial cells is critically involved in TGN1412-mediated effects. Blocking LICOS reduced TGN1412-mediated T-cell proliferation significantly, whereas recombinant LICOS fully conferred TGN1412-mediated T-cell proliferation. Of note, cytokine stimulation enhanced LICOS expression on HUVECs and ICOS-LICOS interaction up-regulated ICOS expression on TGN1412-treated T cells. Hence, we provide a model of positive feedback conferred by ICOS-LICOS interaction between TGN1412-treated T cells and endothelial cells.
authors.affiliation: Junior Research Group, Novel Vaccination Strategies and Early Immune Responses, Paul Ehrlich Institut, Langen, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Weissmüller
authors.forename: Linda Y
authors.initials: LY
authors.lastname: Semmler
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
authors.forename: Stefan
authors.initials: S
authors.lastname: Christians
authors.forename: Jan
authors.initials: J
authors.lastname: Müller-Berghaus
authors.forename: Zoe
authors.initials: Z
authors.lastname: Waibler
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D006801:Humans; D060945:Inducible T-Cell Co-Stimulator Ligand / Q000378:metabolism / Q000502:physiology*; D060889:Inducible T-Cell Co-Stimulator Protein / Q000378:metabolism / Q000502:physiology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D011485:Protein Binding / Q000502:physiology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; C556692:ICOS protein, human; C498514:ICOSLG protein, human; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; C509303:TGN-1412