title: 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.
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138; and Institute of Immunology, Second Military Medical University, Shanghai 200433, People's Republic of China guozh@immunol.org jlstrom@fas.harvard.edu.
authors.forename: Zhenhong
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138; and.
authors.forename: Tamara
authors.initials: T
authors.lastname: Tilburgs
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138; and.
authors.forename: Bonnie
authors.initials: B
authors.lastname: Wong
authors.affiliation: Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138; and guozh@immunol.org jlstrom@fas.harvard.edu.
authors.forename: Jack L
authors.initials: JL
authors.lastname: Strominger
mesh_terms: D000328:Adult; D000368:Aged; D000375:Aging / Q000276:immunology*; D000818:Animals; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007369:Interferon Inducers / Q000008:administration & dosage; D007371:Interferon-gamma / Q000096:biosynthesis; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009374:Neoplasms, Experimental / Q000276:immunology*; D011070:Poly I-C / Q000008:administration & dosage
chemical_list: D016207:Cytokines; D007369:Interferon Inducers; D007371:Interferon-gamma; D011070:Poly I-C
keywords: IL-12; cytokines; interferon-alpha; microarray; volcano plot