Loss of Phagocytic and Antigen Cross-Presenting Capacity in Aging Dendritic Cells Is Associated with Mitochondrial Dysfunction.

Autor:	Chougnet CA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229., Thacker RI; Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229., Shehata HM; Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229., Hennies CM; Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229., Lehn MA; Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229., Lages CS; Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229., Janssen EM; Division of Immunobiology, Cincinnati Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, OH 45229 Edith.Janssen@cchmc.org.
Jazyk:	angličtina
Zdroj:	Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2015 Sep 15; Vol. 195 (6), pp. 2624-32. Date of Electronic Publication: 2015 Aug 05.
DOI:	10.4049/jimmunol.1501006
Abstrakt:	Impaired functionality of dendritic cells (DCs) significantly contributes to decreased adaptive immune responses in aged hosts. The expression of MHC-peptide on the DC surface is the critical first step in T cell priming, but few studies have addressed the effect of aging on Ag acquisition, processing, and presentation by DCs. In this study, we show that aged murine DCs were less efficient in the cross-presentation of cell-associated Ag and subsequently in the cross-priming of CD8(+) T cells than were their young counterparts. The decreased cross-presentation was associated with a reduction in the frequency of CD8α DCs and merocytic (CD8α(-)CD11b(-))DCs that could endocytose cell-associated Ag, as well as the number and the size of the endocytosed particles in the DC that did internalize cell-associated materials. Mechanistically, phagocytic capacity has been associated with mitochondrial activity and membrane potential (Δψm). Aged DCs exhibited profound signs of mitochondrial dysfunction, illustrated by lower Δψm, reduced ATP turnover and coupling efficiency, decreased baseline oxidative phosphorylation, and greater proton leak and reactive oxygen species (ROS) production. Mimicking the aged metabolic phenotype in young DCs by pharmacologic manipulation indicated that the reductions in Δψm and ATP impeded the phagocytic capacity whereas ROS interfered with a later step in the cross-presentation process. Conversely, in vitro scavenging of ROS partially restored cross-presentation by aged DCs. Taken together, these data suggest that improvement of aged DC functionality might be feasible in the elderly by targeting metabolic dysfunction or its downstream sequelae, thereby opening new avenues for enhancing vaccine efficiency in this population. (Copyright © 2015 by The American Association of Immunologists, Inc.)
Databáze:	MEDLINE
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