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Antigen Release Kinetics in the Phagosome Are Critical to Cross-Presentation Efficiency¹

Shanshan W. Howland^* and K. Dane Wittrup^2,*,

^* Department of Biological Engineering and Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139

Cross-presentation of exogenous Ags in MHC class I molecules by dendritic cells is the underlying basis for many developing immunotherapies and vaccines. In the phagosome-to-cytosol pathway, Ags in phagocytosed particles must become freely soluble before being exported to the cytosol, but the kinetics of this process has yet to be fully appreciated. We demonstrate with a yeast vaccine model that the rate of Ag release in the phagosome directly affects cross-presentation efficiency, with an apparent time limit of 25 min postphagocytosis for Ag release to be productive. Ag expressed on the yeast surface is cross-presented much more efficiently than Ag trapped in the yeast cytosol by the cell wall. The cross-presentation efficiency of yeast surface-displayed Ag can be increased by the insertion of linkers susceptible to cleavage in the early phagosome. Ags indirectly attached to yeast through Ab fragments are less efficiently cross-presented when the Ab dissociation rate is extremely slow.

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¹ This work was funded in part by National Institutes of Health Grant AI065824, the Ludwig Institute for Cancer Research, and the Massachusetts Institute of Technology-Harvard Centers of Cancer Nanotechnology Excellence Consortium. S.W.H. is a recipient of a scholarship from Singapore’s Agency for Science, Technology and Research, and of the Margaret A. Cunningham Immune Mechanisms in Cancer Research Fellowship.

² Address correspondence and reprint requests to Dr. K. D. Wittrup, Departments of Biological Engineering and Chemical Engineering, Massachusetts Institute of Technology, Building E19-551, 400 Main Street, Cambridge, MA 02139. E-mail address: wittrup{at}mit.edu

³ Abbreviations used in this paper: DC, dendritic cell; CatS, Cathepsin S; scFv, single-chain variable fragment; ER, endoplasmic reticulum; RIPA, radioimmunoprecipitation assay.