To improve the success of in vitro maturation of monocytes to effective dendritic cells, Han and Hanlon et al. found that the presence of activated (P-selectin-presenting) platelets rapidly matured murine monocytes to a CD11c+, MHC-II+, CD80/86+ phenotype with faster and (for apoptotic cell antigen) improved cross-presenting capability compared to cytokine-matured, bone marrow-derived DCs. Human monocytes were similarly activated. Plate-bound P-selectin and agonist PSGL-1 antibody also induced monocyte differentiation, and platelet-monocyte interaction stimulated multiple signaling pathways leading to NFκB translocation and calcium influx, explaining the long hidden mechanism behind ECP.
Contributed by Ed Fritsch
ABSTRACT: Dendritic cells (DCs) are adept at cross-presentation and initiation of antigen-specific immunity. Clinically, however, DCs produced by in vitro differentiation of monocytes in the presence of exogenous cytokines have been met with limited success. We hypothesized that DCs produced in a physiological manner may be more effective and found that platelets activate a cross-presentation program in peripheral blood monocytes with rapid (18 hours) maturation into physiological DCs (phDCs). Differentiation of monocytes into phDCs was concomitant with the formation of an "adhesion synapse," a biophysical junction enriched with platelet P-selectin and monocyte P-selectin glycoprotein ligand 1, followed by intracellular calcium fluxing and nuclear localization of nuclear factor kappaB. phDCs were more efficient than cytokine-derived DCs in generating tumor-specific T cell immunity. Our findings demonstrate that platelets mediate a cytokine-independent, physiologic maturation of DC and suggest a novel strategy for DC-based immunotherapies.
Author Info: (1) Department of Chemical and Environmental Engineering, School of Engineering and Applied Science, Yale University, New Haven, CT 06511, USA. (2) Department of Dermatology, Schoo
Author Info: (1) Department of Chemical and Environmental Engineering, School of Engineering and Applied Science, Yale University, New Haven, CT 06511, USA. (2) Department of Dermatology, School of Medicine, Yale University, New Haven, CT 06511, USA. (3) Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06511, USA. (4) Department of Biomedical Engineering, School of Engineering and Applied Science, Yale University, New Haven, CT 06511, USA. (5) Department of Dermatology, School of Medicine, Yale University, New Haven, CT 06511, USA. (6) Department of Dermatology, School of Medicine, Yale University, New Haven, CT 06511, USA. (7) Department of Dermatology, School of Medicine, Yale University, New Haven, CT 06511, USA. (8) Department of Dermatology, School of Medicine, Yale University, New Haven, CT 06511, USA. (9) Yale Flow Cytometry Facility, School of Medicine, Yale University, New Haven, CT 06511, USA. (10) Yale CINEMA Lab, School of Medicine, Yale University, New Haven, CT 06511, USA. (11) Yale CINEMA Lab, School of Medicine, Yale University, New Haven, CT 06511, USA. (12) Department of Chemical and Environmental Engineering, School of Engineering and Applied Science, Yale University, New Haven, CT 06511, USA. Department of Dermatology, School of Medicine, Yale University, New Haven, CT 06511, USA. Department of Immunobiology, School of Medicine, Yale University, New Haven, CT 06511, USA. Department of Biomedical Engineering, School of Engineering and Applied Science, Yale University, New Haven, CT 06511, USA. (13) Department of Dermatology, School of Medicine, Yale University, New Haven, CT 06511, USA.
