Investigation into regulation of immune responses by NK cells and NKT cells

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I have been analyzed target-recognizing and cytotoxic mechanisms of NK cells and NKT cells to elucidate the possibility to regulate immune responses by these cells and/or their functional molecules.1. TNF-related apoptosis-inducing ligand (TRAIL) is the critical cytotoxic molecule of immature NK cells, and which play critical roles in self-defense of infant mice. We also demonstrated that TRAIL-expressing NK cells in the liver of adult mice are immature NK cells potentially developing into mature NK cells.2. TRAIL is a critical molecule in NK cell mediated tumor surveillance. To utilize TRAIL to tumor therapy, we newly established agonistic monoclonal antibody to DR5 (death-inducing TRAIL receptor) (MD5-1). Treatment with MD5-1 induces tumor rejection of TRAIL-sensitive tumor cells by apoptosis induction, and also induces tumor specific T cell responses, and which results in the rejection of TRAIL-resistant tumor variants.3. We demonstrated that IOCS play a role as costimulatory molecules in NKT cell activation, which augments cytokines production and cytotoxic activity.4. Specific ligand-activated NKT cells temporally internalize inhibitory NK cell receptor (CD94/NKG2), and these NKT cells demonstrate dramatically augmented cytokines production and anti-tumor effects when re-stimulated with α-Galactosylceramide (NKT cell specific ligand). We also demonstrated that this regulation is mediated by IFN-γ. These results suggested that combined therapy of NKT cell specific ligand and/or inhibition of NK cell receptor-mediated signal augments NKT cell mediated anti-tumor effects.5. We reported that TRAIL is expressed on tumor infiltrating T cells in BCG-treated bladder cancers in human, and suggested the possible contribution of TRAIL to therapeutic effect of BCG therapy.6. TWEAK, one of the member of TNF super family as TRAIL, is expressed on macrophages and plays important roles in inhibition of tumor growth and immunological tumor surveillance.