Influenza is a public health concern, especially for the elderly. While influenza vaccination is efficacious in the young, it offers only limited protection in the elderly. Thus, it becomes imperative to understand age-related changes in the primary response to influenza infection. Studies presented in this dissertation identified potential age-related defects in natural killer (NK) cell function during influenza infection. We showed that NK cells from aged mice were reduced and had impaired function and altered phenotype in lungs during influenza infection. Aged NK cells demonstrated decreased IFN-γ production but not degranulation after influenza infection. However, after ex vivo activation with YAC-1 cells, aged NK cells demonstrated both reduced IFN-γ production and degranulation. IFN-γ was also reduced in aged NK cells after activation with anti-NKp46 and soluble cytokines. IFN-β, and IL-12p40 mRNA expression was not significantly different from that observed in adult mice. Analysis of NK cell subsets indicated that aged mice had more immature and less terminally mature NK cells that were available to respond during the early days of the infection. Thus, we investigated the age-related defects in NK cell tissue and subset distribution, development and function in resting uninfected mice. Our findings indicate that aged mice have reduced NK cells in most peripheral tissues but have increased NK cells in the bone marrow. Analysis of NK cell subsets based on CD11b and CD27 expression revealed that the reduction of NK cells in the periphery was attributed to a specific reduction of the most mature, CD11b+ CD27- NK cells and the accumulation of NK cells in the bone marrow was attributed to a specific increase of the immature, CD11b- CD27+ NK cells. A detailed analysis of the stages of NK cell development in the bone marrow revealed that NK cells go normally through the stages I-IV of development, but they accumulated in the stage IV and could not further mature. We related this defect with the reduced levels of proliferating NK cells in the bone marrow of aged mice. We further showed that CD11b+ CD27- NK cells exhibit reduced survival in the aged peripheral tissues. Finally with an extensive phenotypic characterization of young and aged NK cells we have shown that impaired NK cell function is not related with their altered Ly49 receptor repertoire, but rather with their maturation status. Indeed, aged NK cells that had acquired the appropriate Ly49 receptors were less responsive, and were composed of more immature NK cells. Overall we provide data that support for an age-related defective development of NK cells.
Read
