Death decoy receptor TR6/DcR3 inhibits T cell chemotaxis in vitro and in vivo.
TR6/DcR3 is a secreted molecule belonging to the TNFR family. Its ligands are LIGHT, Fas ligand, and TL1A, all TNF family members. TR6 is expressed in some tumors and is hypothesized to endow tumor cells with survival advantages by blocking Fas-mediated apoptosis. It can also inhibit T cell activation by interfering with two-way T cell costimulation between LIGHT and HveA. In this study, we discovered a novel function of TR6: inhibition of T cell chemotaxis. Human T cells pretreated with soluble or solid-phase TR6-Fc showed compromised migration toward CXCL12/stromal cell-derived factor 1alpha in vitro in a Transwell assay. Such an effect could also be observed in T cells pretreated with soluble or solid-phase HveA-Fc or anti-LIGHT mAb, suggesting that LIGHT reverse signaling was likely responsible for chemotaxis inhibition. TR6 pretreatment also led to T cell chemotaxis suppression in vivo in the mice, confirming in vivo relevance of the in vitro observation. Mechanistically, a small GTPase Cdc42 failed to be activated after TR6 pretreatment of human T cells, and further downstream, p38 mitogen-activated protein kinase activation, actin polymerization, and pseudopodium formation were all down-regulated in the treated T cells. This study revealed a previously unknown function of TR6 in immune regulation, and such an effect could conceivably be explored for therapeutic use in controlling undesirable immune responses.
D000199:Actins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000328:Adult; D000818:Animals; D002464:Cell Migration Inhibition; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000276:immunology*; D015536:Down-Regulation / Q000276:immunology; D004789:Enzyme Activation / Q000276:immunology; D006801:Humans; D007275:Injections, Intravenous; D008213:Lymphocyte Activation / Q000276:immunology; D020935:MAP Kinase Signaling System / Q000276:immunology; D008562:Membrane Glycoproteins / Q000008:administration & dosage* / Q000494:pharmacology*; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D011956:Receptors, Cell Surface / Q000008:administration & dosage*; D018124:Receptors, Tumor Necrosis Factor; D053323:Receptors, Tumor Necrosis Factor, Member 6b; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology* / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D020764:cdc42 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D000199:Actins; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D053323:Receptors, Tumor Necrosis Factor, Member 6b; D011993:Recombinant Fusion Proteins; C505911:TNFRSF6B protein, human; C505914:TNFSF14 protein, human; C505915:Tnfsf14 protein, mouse; D053326:Tumor Necrosis Factor Ligand Superfamily Member 14; D014409:Tumor Necrosis Factor-alpha; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020764:cdc42 GTP-Binding Protein