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Degree

Doctor of Philosophy, Ohio State University, Veterinary Biosciences, 2002.

Abstract

Through their early production of cytokines and chemokines and their ability to lyse target cells without prior sensitization, natural killer (NK) cells are crucial components of the innate immune system. Human NK cells can be divided into two subsets based on their cell-surface density of the CD56 marker, CD56^bright and CD56^dim , each with distinct phenotypic and functional properties. Regulation of NK cell activation and homeostasis is regulated to a large degree by cytokines, and NK cells constitutively express a variety of cytokine receptors. During the early, innate immune response to infection, monocyte-derived cytokines (monokines), stimulate NK cells to produce immunoregulatory cytokines that are important to the host's early defense. Interleukin-1beta is one such monokine produced early in the immune response to various infections, but its role in promoting human NK cell cytokine production is unknown. Stimulation with this cytokine was found to induce abundant levels of CD56^bright NK cell-derived IFN-gamma, a cytokine that is critical for the elimination of obligate intracellular pathogens. Further studies demonstrated that in response to various combinations of additional monokines or when co-cultured with activated monocytes, the CD56^bright NK cell subset produces significantly greater levels of multiple cytokines than do CD56^dim NK cells. These results suggest that human CD56^bright NK cells have a unique functional role in the innate immune response as the primary source of NK cell-derived immunoregulatory cytokines. In order for NK cells to be maintained and available to fight infection in vivo, the homeostasis of these lymphocytes must be carefully regulated. However, very little is known about the factors controlling the survival of mature NK cells. We hypothesized that interleukin (IL)-15 may be a survival factor for NK cells. Based on results from two separate in vivo models, we have conclusively demonstrated that IL-15 is requisite for the survival of mature NK cells in vivo. Collectively, these studies provide new insight into the role of cytokines in the activation and homeostasis of NK cells and evidence for distinct functions of human NK cell subsets during the immune response.

Subject Headings

Health Sciences, Immunology

Keywords

Immunology; Natural Killer Cell; Innate Immunity; Cytokines

Advisor

Michael A Caligiuri

Document number: osu1021398366
Permalink: http://rave.ohiolink.edu/etdc/view?acc_num=osu1021398366

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