Dysfunction of dendritic cells in aged C57BL/6 mice leads to failure of natural killer cell activation and of tumor eradication

Abstract

The reciprocal activation of dendritic cells (DCs) and natural killer cells (NKs) plays a key role in both innate and adaptive immunity. The effect of aging on this cross-talk, a critical step in virus disease control and tumor immunology, has not been reported. Splenic DCs and NKs were purified from both young and old C57BL/6 mice and cocultured in the presence of polyinosinic:polycytidylic acid (poly I:C). The resulting activation of NKs was measured as expression of CD69 and secretion of IFN-γ. However, DCs from old mice could not activate NKs from either young or old mice in vitro or in vivo. In contrast, DCs from young mice efficiently activated NKs from both young and old mice. DCs from old mice were deficient in poly I: C-stimulated secretion of IL-15, IL-18, and IFN-α. Gene expression analysis revealed many other differences between DCs of old and young mice. Young mice strongly eradicated MHC class I-negative NK-sensitive RMA-S lymphoma mutant tumor cells, but old mice did not, in concert with the previous report that mousepox kills aged, but not young, C57BL/6 mice. Furthermore, a similar dysfunction of DC and its key role in NK activation was found in 27 out of 55 healthy human donors. A few years later, the reciprocal interaction of DCs and NKs during viral infection was also described (3). Cytokines from DCs as well as cell-cell contact were shown to enhance NK function. DCs secreted IL-12 and IL-18, which promoted cytokine production by NKs (4, 5). Further, membrane-bound IL-15/15Rα on DCs is important in promoting NK survival and proliferation (6-8), and type I IFNs are crucial in the induction of NK cytotoxicity. In addition, some surface molecules on DCs-for example, CD40, CD48, CD70, CD80, CD86, major histocompatibility complex class I-related chain A/B (MICA/B), leukocyte function-associated Ag-1 (LFA-1), and chemokine (C-X3-C motif) ligand 1 (CX3CL1)-have been reported to be involved in the effect of DCs on NKs (1).It is well known that aged humans are more susceptible to malignancies and infectious diseases and less responsive to vaccination because of immunosenescence-that is, progressive deterioration in immune function with aging. Increasing evidence shows aging affects many cells in both innate immunity and adaptive immunity (9). For example, impairment of DC and macrophage functions, including phagocytic activity, cytokine secretion, wound repair, and antigen presentation, were observed (10, 11). In T cells, a shift from the naïve to memory phenotype, a decreased proliferative response, and impaired cytolytic activity were found (12). Some of these defects in cell functions are intrinsic, whereas others might be the consequence of the complicated interactions between immune cells (13). As key cells in innate immunity, functional changes in both NKs and DCs with aging were described. For example, increased numbers of NKs, decreased NK cytotoxicity on a per-cell basis, and reduced levels of cytokines and chemokines upon activation were reported in humans (14). Importantly, aged C57BL/6 mi...

Metabolic and Phenotypic Differences between Mice Producing a Werner Syndrome Helicase Mutant Protein and Wrn Null Mice

“…In contrast, IL-18 is significantly decreased in the serum of Wrn Δhel/Δhel mice compared to WT animals, whereas Wrn -/- mice showed a similar trend. A lower secretion of IL-18 has been shown to be an important factor in the dysfunction of dendritic cells in aged C57BL/6 mice [ 40 ]. Dendritic cells are central in regulating both innate and acquired immunity.…”

Alcohol, aging, and innate immunity

“…Chronic alcohol consumption in animals blunts the ability of DCs to up-regulate costimulatory molecules [227,[232][233][234][235]. In aged animals and humans, the production of proinflammatory cytokines by DCs, including type I IFNs, IL-6, and TNF-a, are decreased, but the level of the anti-inflammatory cytokine IL-10 is greater than in younger hosts [44,222,[236][237][238][239][240][241]. However, not all studies support the conclusion that DCs from older hosts are unable to promote inflammation; some studies have reported no difference in the production of those cytokines with age, or an even an increase in IL-6 and TNF-a by DCs from older, compared with younger, humans and rodents [46,214,217,[242][243][244].…”

Interleukin-15 Dendritic Cells Harness NK Cell Cytotoxic Effector Function in a Contact- and IL-15-Dependent Manner

“…Nevertheless, a growing body of research indicates that the therapeutic activity of DC cancer vaccination does not exclusively rely on engagement of the adaptive immune arm, but also on its ability to harness innate anti-tumor effector cells [ 4 , 5 ]. The importance of NK cells in the anti-tumor activity of DC-based immunotherapy has been demonstrated in several animal studies, some of which have pointed to an indispensable role for NK cells in this respect [ 11 – 18 ]. In human clinical trials [ 19 – 21 ], the induction of NK cell immune responses by DC vaccination was shown to be associated with favorable clinical outcome, whereas such correlation has not been consistently reported for DC vaccine-induced T-cell immunity.…”