The TNF superfamily cytokine receptor Death Receptor 3 is a costimulatory molecule for iNKT cells

Abstract

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