The TNF superfamily cytokine receptor Death Receptor 3 is a costimulatory molecule for <i>i</i>NKT cells

Abstract Invariant NKT (iNKT) cells are a small population of thymus-generated T lymphocytes with innate-like phenotype and function that play disproportionally important role in immune regulation surveillance. iNKT generated upon strong agonistic TCR signaling by glycolipid-loaded CD1d molecules, which differs from conventional positively selected weak engagement peptide-loaded MHC molecules. Whether also distinct their costimulatory requirement, however, has remained largely unresolved. Here, we report the TNF superfamily receptor death 3 (DR3) plays previously unappreciated peripheral cell activation. We found co-injection anti-DR3 antibodies significantly augmented activation proliferation mature α-GalCer injected mice. Moreover, co-injected mice dramatically increased expression proinflammatory cytokines, resulting severe thymic atrophy. The DR3 effect was strictly dependent on cells, because iNKT-deficient Traj18−/−mice were refractory to costimulation-induced inflammation. Because ligation alone did not suffice activate exerted its effects only context costimulation, these results strongly support being new bona fidecostimulatory molecule for cells. Considering interest utilizing adoptive therapies as anti-tumor bioreagents, employing tool boost immunity will open venues translational clinical research. This work supported Intramural Research Program NIH, National Cancer Institute, Center Research.