T g Mediated Expansion of Human - IL-18 Cells in + CD11c bright Involvement of CD56

gd T cells are considered to be innate lymphocytes that play an important role in host defense against tumors and infections. We recently reported that IL-18 markedly amplified gd T cell responses to zoledronate (ZOL)/IL-2. In an extension of this finding, we analyzed the mechanism underlying the IL-18–mediated expansion of gd T cells. After incubation of PBMCs with ZOL/IL-2/IL-18, the majority of the cells expressed gd TCR, and the rest mostly exhibited CD56 bright CD11c + under the conditions used in this study. CD56 bright CD11c + cells were derived from a culture of CD56 int CD11c + cells and CD14 + cells in the presence of IL-2 and IL-18 without the addition of ZOL. They expressed IL-18Rs, HLA-DR, CD25, CD80, CD83, CD86, and CD11a/CD18. In addition, they produced IFN- g , TNF- a , but not IL-12, when treated with IL-2/IL-18, and they exerted cytotoxicity against K562 cells, thus exhibiting characteristics of both NK cells and dendritic cells. Incubation of purified gd T cells with CD56 bright CD11c + cells in the presence of ZOL/IL-2/IL-18 resulted in the formation of massive cell clusters and led to the marked expansion of gd T cells. However, both conventional CD56 2 /int CD11c high dendritic cells induced by GM-CSF/IL-4 and CD56 + CD11c 2 NK cells failed to support the expansion of gd T cells. These results strongly suggest that CD56 bright CD11c + cells play a key for the apparently paradoxical actions sometimes observed in IL-18. In the current study, we demonstrate that IL-2/IL-18 efficiently generates and expands CD56 bright CD11c + cells, which functionally and phenotypically overlap with NK cells and DCs and are essential in the amplification of gd T cell responses to zoledronate or 2-methyl-3-butenyl-1-pyrophosphate (2M3BPP), an IPP In addition, we characterize CD56 bright CD11c + cells and discuss a possible therapeutic use of ZOL/IL-2/IL-18 in the treatment of patients with cancer.

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