Loss of phagocytic and antigen cross-presenting capacity in aging DCs is associated with mitochondrial dysfunction

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 antigen (Ag) acquisition, processing, and presentation by DCs. Here 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 their young counterparts. The decreased cross-presentation was associated with a reduction in the frequency of CD8αDCs 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 (OXPHOS), and greater proton leak and 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 while ROS interfered with a later step in the cross-presentation process. Conversely, in vitro scavenging of ROS partially restored cross-presentation by aged DCs. 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.