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The Function and Homeostasis of Natural Killer Cells in Aging

Shehata, Hesham M, Ph.D.
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447158135

Abstract Details

2015, PhD, University of Cincinnati, Medicine: Immunology.
Aging is a complex process that negatively affects a wide variety of physiological functions, including the development and maintenance of robust immune responses. Developing successful strategies that promote improved immune responses in the elderly against infectious pathogens and cancers that cause high mortality represents a growing public health priority. Natural killer (NK) cells play a critical role in eliminating tumor cells and viral infections, both of which occur at a high incidence in the elderly population. Aging has a considerable negative impact on the function and development of NK cells. These defects attenuate NK cell cytotoxicity to virus infected cells and tumors. Thus, studies to determine the causes of aged-related NK cell dysfunctions are critically required to address the health needs of a growing elderly population. The precise mechanism(s) underlying the impaired maturation and function of NK cells in aging remain unidentified. This dissertation aims to fill this gap in knowledge by evaluating whether key factors known to be important in NK cell biology could be dysregulated in aging, thus impairing their functional maturation. Importantly it highlights novel avenues for research in the field geared at discovering the specific factor(s) that impair the function and terminal maturation of NK cells in aging. Herein, we provide evidence that the aged environment and in particular, the aged BM microenvironment contributes to the impaired maturation and function of NK cells. NK cells derived from both young and aged BM cells adopted an impaired maturation phenotype in an aged host i.e. were hyporesponsive to stimuli in vitro, while adopting an augmented maturation phenotype following transfer in young hosts. In our pursuit to identify the environmental factor(s) that may contribute to this phenotype, we observed a differential pattern of expression of key transcription factors including a decrease in T-bet and Eomes which are known to regulate NK cell maturation and function. Importantly, the environment in which NK cells developed played an important role in regulating the expression of both T-bet and Eomes. One of the major factors implicated in regulating T-bet and Eomes expression and NK cell maturation is IL-15. Our data suggest that deficiencies in IL-15 production or IL-15 signaling in aging are unlikely to be the mechanisms underlying the impaired maturation of NK cells as administering a large quantity of IL-15/IL-15Ra complex to aged mice did not augment NK cell maturation in the BM, despite their capacity to expand in response to IL-15. On another front, we identified for the first time a profound presence of MHC-I low cells in the lymphoid organs of aged mice. These cells have a late-apoptotic phenotype with fewer organelles and some of which appear to be necrotic cells. As MHC-I deficiency imposes NK cell hyporesponsiveness, it will be interesting to evaluate whether the presence of these cells in the aged environment contribute to the hyporesponsiveness of NK cells
Claire Chougnet, Ph.D. (Committee Chair)
Fred Finkelman, M.D. (Committee Member)
David Hildeman, Ph.D. (Committee Member)
Edith Janssen, Ph.D. (Committee Member)
James Mulloy, Ph.D. (Committee Member)
200 p.
Immunology
Natural Killer Cells; Aging; Maturation; Aged Environment; Development

Recommended Citations

Citations

  • Shehata, H. M. (2015). The Function and Homeostasis of Natural Killer Cells in Aging [Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447158135

    APA Style (7th edition)

  • Shehata, Hesham. The Function and Homeostasis of Natural Killer Cells in Aging. 2015. University of Cincinnati, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447158135.

    MLA Style (8th edition)

  • Shehata, Hesham. "The Function and Homeostasis of Natural Killer Cells in Aging." Doctoral dissertation, University of Cincinnati, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1447158135

    Chicago Manual of Style (17th edition)

ucin1447158135
346
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This open access ETD is published by University of Cincinnati and OhioLINK.