The host environment is responsible for aging-related functional NK cell deficiency.
NK cells play an important role in immunity against infection and tumors. Aging-related functional NK cell deficiency is well documented in humans and mice. However, the mechanism for this is poorly understood. Using an adoptive transfer approach in mice, we found that NK cells from both young and aged mice responded vigorously to priming by pathogen-derived products after being cotransferred into young mice. In contrast, NK cells from young mice responded poorly to priming by pathogen-derived products after being transferred to aged mice. In addition to defects in NK cell priming, maturation of NK cells under steady-state conditions is also impaired in aged mice, resulting in a decreased proportion of CD27(-) mature NK cells. We found that bone marrow from young and aged mice gave rise to CD27(-) mature NK cells similarly in young mixed bone marrow chimeric mice. Furthermore, by using a novel bone marrow transfer approach without irradiation, we found that after being transferred to aged mice, bone marrow from young mice gave rise to NK cells with maturation defects. Finally, we found that aging-related functional NK cell deficiency was completely reversed by injecting soluble IL-15/IL-15Rα complexes. In contrast, blockade of IL-10 signaling, which broadly augments inflammatory responses to pathogen-derived products, had little effect on aging-related defects in NK cell priming. These data demonstrate that the aged host environment is responsible for aging-related functional NK cell deficiency. Additionally, our data suggest that IL-15 receptor agonists may be useful tools in treating aging-related functional NK cell deficiency.
Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109.
Bo-Chin
BC
Chiu
Brian E
BE
Martin
Valerie R
VR
Stolberg
Stephen W
SW
Chensue
D019264:Adoptive Transfer; D000375:Aging / Q000276:immunology*; D000818:Animals; D001853:Bone Marrow / Q000276:immunology; D001854:Bone Marrow Cells / Q000166:cytology; D049109:Cell Proliferation; D016922:Cellular Senescence / Q000276:immunology; D016753:Interleukin-10 / Q000037:antagonists & inhibitors; D019409:Interleukin-15 / Q000276:immunology / Q000378:metabolism*; D053720:Interleukin-15 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology*; D037181:Lectins, C-Type; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011971:Receptors, Immunologic / Q000096:biosynthesis; D015398:Signal Transduction / Q000276:immunology; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism
D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; C451496:Klrg1 protein, mouse; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D016753:Interleukin-10