title: Thromboxane A2 acts as tonic immunoregulator by preferential disruption of low-avidity CD4+ T cell-dendritic cell interactions.
abstract: Interactions between dendritic cells (DCs) and T cells control the decision between activation and tolerance induction. Thromboxane A2 (TXA2) and its receptor TP have been suggested to regulate adaptive immune responses through control of T cell-DC interactions. Here, we show that this control is achieved by selectively reducing expansion of low-avidity CD4(+) T cells. During inflammation, weak tetramer-binding TP-deficient CD4(+) T cells were preferentially expanded compared with TP-proficient CD4(+) T cells. Using intravital imaging of cellular interactions in reactive peripheral lymph nodes (PLNs), we found that TXA2 led to disruption of low- but not high-avidity interactions between DCs and CD4(+) T cells. Lack of TP correlated with higher expression of activation markers on stimulated CD4(+) T cells and with augmented accumulation of follicular helper T cells (TFH), which correlated with increased low-avidity IgG responses. In sum, our data suggest that tonic suppression of weak CD4(+) T cell-DC interactions by TXA2-TP signaling improves the overall quality of adaptive immune responses.
authors.affiliation: Theodor Kocher Institute, University of Bern, 3012 Bern, Switzerland.
authors.forename: Federica
authors.initials: F
authors.lastname: Moalli
authors.affiliation: Institute of Immunobiology, Cantonal Hospital St. Gallen, CH-9007 St. Gallen, Switzerland.
authors.forename: Jovana
authors.initials: J
authors.lastname: Cupovic
authors.affiliation: Theodor Kocher Institute, University of Bern, 3012 Bern, Switzerland.
authors.forename: Flavian
authors.initials: F
authors.lastname: Thelen
authors.affiliation: Theodor Kocher Institute, University of Bern, 3012 Bern, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Halbherr
authors.affiliation: Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation and Research Center for Advanced Immunology, Kyushu University, Fukuoka 812-8582, Japan Division of Immunogenetics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation and Research Center for Advanced Immunology, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Fukui
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Shuh
authors.initials: S
authors.lastname: Narumiya
authors.affiliation: Institute of Immunobiology, Cantonal Hospital St. Gallen, CH-9007 St. Gallen, Switzerland.
authors.forename: Burkhard
authors.initials: B
authors.lastname: Ludewig
authors.affiliation: Theodor Kocher Institute, University of Bern, 3012 Bern, Switzerland jstein@tki.unibe.ch.
authors.forename: Jens V
authors.initials: JV
authors.lastname: Stein
mesh_terms: D000818:Animals; D000915:Antibody Affinity / Q000187:drug effects*; D015415:Biomarkers / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*; D002450:Cell Communication / Q000187:drug effects*; D002645:Chickens; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D006649:Histocompatibility Antigens / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis; D007155:Immunologic Factors / Q000494:pharmacology*; D007249:Inflammation / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D018655:Lymphocyte Count; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D036641:Microscopy, Fluorescence, Multiphoton; D010047:Ovalbumin / Q000276:immunology; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000172:deficiency / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology; D013928:Thromboxane A2 / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D006649:Histocompatibility Antigens; D007074:Immunoglobulin G; D007155:Immunologic Factors; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013928:Thromboxane A2; D010047:Ovalbumin