Project Summary/Abstract The immune system serves as a host-defense mechanism against invading pathogens and transformed cells through an intricate network of signaling molecules and specialized cells. Natural Killer (NK) cells are cytotoxic lymphocytes that kill virus-infected and cancer cells. They are an integral component of tumor-immune surveillance. However, Natural Killer cells from cancer patients are rendered dysfunctional1-10. Finding key factors that regulate NK cell cytotoxic function is vital to understand the mechanistic alterations leading into NK cell dysfunction in cancer. Various studies show that NK cell cytotoxicity can be mediated by cytokines including: IL- 2, GM-CSF, IL-15, IL-21, and TGF-β11-20, all of which are regulated by NF-κB c-Rel21-23. NF-κB c- Rel is a transcription factor that is constitutively expressed in myeloid and lymphocytic lineages24. Although c-Rel has been reported to promote T cell proliferation and cytokine production24-27, the role of c-Rel in NK cells remains unknown. Preliminary studies utilizing purified murine WT and c- Rel-/- NK cells, show that deficiency in c-Rel expression results in reduced perforin expression and impaired anti-tumor function in murine NK cells. Similarly, inhibition of c-Rel with specific small molecule inhibitor, lead to decreased perforin expression and impaired anti-tumor cytotoxicity of human NK cells. We therefore seek to define the role of c-Rel in regulating mouse and human NK cell anti-tumor cytotoxic activity. The first aim will define the role of c-Rel in regulating NK cell cytotoxic function. The second aim will investigate the mechanism by which c-Rel regulates NK cells ability to kill tumor cells. Completion of these aims will define the mechanism-driven c-Rel regulation of NK cell cytotoxic function.