Dendritic cell internalization of alpha-galactosylceramide from CD8 T cells induces potent antitumor CD8 T cell responses
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.
|Authors||Choi, D.; Kim, K. S.; Yang, S. H.; Chung, D. H.; Song, B.; Sprent, J.; Cho, J. H.; Sung, Y. C.|
|Publisher Name||CANCER RESEARCH|
|DOI||0008-5472.CAN-11-1459 [pii] 10.1158/0008-5472.CAN-11-1459|
|URL link to publisher's version||http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22028323|
|OpenAccess link to author's accepted manuscript version||https://publications.gimr.garvan.org.au/open-access/11204|