Emerging evidence suggests that gamma delta (γd) T cells play a critical role in bridging innate and adaptive immune responses, yet the mechanisms responsible for these effects are uncertain. In this study we show that isopentenyl pyrophosphate (IPP) activated γd T lymphocytes induce cytolytic function of Ig stimulated NK cells. These "costimulated" NK cells up regulate the CD54 and CD69 markers of cellular activation and also display enhanced cytotoxicity against squamous cell carcinoma of the head and neck (SCCHN). Based on our findings that "co stimulation" of Ig primed NK cells by γδ T lymphocytes requires cell-to-cell contact, we performed a comprehensive expression analysis of TNFSF members expressed on the surface of IPP activated γδ T lymphocytes, and found that these cells express high levels of 4-1BB ligand. Stimulation of Ig primed NK cells with 4-1BBL but not mock transfected P815 cells, induces up regulation of CD54 and CD69 and blockade of 4-1BB/4-1BBL interaction by soluble 4-1BB fusion protein decreased activation of NK co-cultured with γδ T lymphocytes. In addition, we observed that NK cells cultured with Ig/γδ T lymphocytes up regulate NKG2D and anti-NKG2D mAb blockade partially abrogates the cytolytic effects of these "costimulated" NK cells against SCCHN. Taken in concert, our data indicate that γδ T lymphocytes induce activation of Ig primed NK cells through coordinated 4-1BB -4-1BBL interactions and up regulation of targeted cell death pathways.