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.