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Phagocytosis Induces Lysosome Remodeling and Regulated Presentation of Particulate Antigens by Activated Dendritic Cells¹

Jayakar V. Nayak^*,,, David A. Hokey^*,, Adriana Larregina^*,, Yukai He^*,, Russell D. Salter, Simon C. Watkins and Louis D. Falo, Jr^2,*,

^* Department of Dermatology, Department of Immunology, Department of Otolaryngology, and Department of Cell Biology and Physiology and Center for Biologic Imaging, University of Pittsburgh School of Medicine, Pittsburgh, PA 15217

Immunization with particulate Ag effectively induces antitumor and antiviral T cell-mediated immunity. Immature dendritic cells (DCs) efficiently internalize, process, and present a variety of particulate Ags; however, previously published data suggest that both the uptake of soluble Ag through micropinocytosis, and phagocytosis of particulates are significantly curtailed in activated DC populations. In this study, we demonstrate that although macropinocytosis of soluble Ag is diminished following DC activation, subsets of DCs in activated DC populations retain the ability to actively phagocytose particulate Ags. Live cell imaging of activated DCs reveals that phagocytosis of particulates can result in cytoskeletal remodeling and perinuclear lysosome cluster disruption in a time-dependent manner. Interestingly, our results suggest that in activated DC populations, presentation of phagocytosed particulate Ags is dependent on the nature of the activation signal. These results provide direct evidence of functional heterogeneity in DC populations and contribute to the development of particle-based immunization strategies.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by grants from National Institutes of Health National Cancer Institute, National Institute of Arthritis and Musculoskeletal and Skin Diseases, and National Institute of Allergy and Infectious Diseases (to L.D.F.).

² Address correspondence and reprint requests to Dr. Louis D. Falo, Jr., Department of Dermatology, University of Pittsburgh School of Medicine, 145 Lothrop Hall, Pittsburgh, PA 15217. E-mail address: lof2{at}pitt.edu

³ Abbreviations used in this paper: DC, dendritic cell; MIIC, MHC class II compartment; LAMP, lysosome-associated membrane protein; ER, endoplasmic reticulum; BMDC, bone marrow-derived DC; m, murine; RT, room temperature; man-PAA, mannosylated polyacrylamide; CCD, cytochalasin D; CPP, cytometric particle phagocytosis; DAPI, 4',6'-diamidino-2-phenylindole; CMFDA, 5-chloromethylfluorescein diacetate; int, intermediate; MFI, mean fluorescence intensity; PCHO, paraformaldehyde.

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