Publications

Abstract

Dendritic cells (DC) present alphaGalactosylceramide (alphaGalCer) to invariant T cell receptor-expressing natural killer T cells (iNKT) activating these cells to secrete a variety of cytokines, which in turn results in DC maturation and activation of other cell types, including NK cells, B cells, and conventional T cells. In this study, we demonstrated that alphaGalCer-pulsing of antigen-activated CD8 T cells before adoptive transfer to tumor-bearing mice caused a marked increase in donor T cell proliferation, precursor frequency, and cytotoxic lymphocyte activity. This effect was IL-2 dependent and involved both NKT and DC, since mice lacking IL-2, NKT and DC lacked any enhanced response to adoptively transferred alphaGalCer-loaded CD8 T cells. iNKT activation was mediated by transfer of alphaGalCer from the cell membrane of the donor CD8 T cells onto the alphaGalCer receptor CD1d which is present on host DC. alphaGalCer transfer was increased by prior activation of the donor CD8 T cells and required AP2-mediated endocytosis by host DC. In addition, host iNKT cell activation led to strong IL-2 synthesis, thereby increasing expansion and differentiation of donor CD8 T cells. Transfer of these cells led to improved therapeutic efficacy against established solid tumors in mice. Thus, our findings illustrate how alphaGalCer loading of CD8 T cells after antigen activation in vitro may leverage the therapeutic potential of adoptive T cell therapies.