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Dendritic cell internalization of alpha-galactosylceramide from CD8 T cells induces potent antitumor CD8 T cell responses

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.

Type Journal
Authors Choi, D.; Kim, K. S.; Yang, S. H.; Chung, D. H.; Song, B.; Sprent, J.; Cho, J. H.; Sung, Y. C.
Garvan Authors Prof Jonathan Sprent
Publisher Name CANCER RES
Published Date 2011-12-01 00:00:00
Published Volume 71
Published Issue 24
Published Pages 7442-51
URL http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=22028323
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?11204_11811/11 Choi Cancer Res.pdf