Mullen, Alexandra
(2024)
Elucidating the Mechanistic Role of ADAM17 in IL-18 Induced “Memory-Like” Natural Killer Cell Differentiation and Helper Function.
Master's Thesis, University of Pittsburgh.
(Unpublished)
Abstract
HIV-1 infection causes a skewed phenotypic and functional repertoire of natural killer (NK) cells, which continues to be present in people living with HIV-1 (PLWH) following effective control of HIV-1 viremia with long-term antiretroviral therapy (ART). This is highlighted by the expansion of a rare and highly differentiated population of ADCC hyper-responsive CD16+ FcR- NK cells that exhibit adaptive immune characteristics, such as immunological memory. In addition to the FcR- NK population, NK cells can differentiate into a cytokine-induced “memory-like” population that lacks CD16 expression and acquires characteristics more commonly associated with T helper cells. Our lab has shown that IL-18 stimulation proved to be critical for distinguishing the capacity of an NK cell to differentiate into either a cytolytic FcR- NK cell or a helper -like NK cell as FcR- cells are rendered unresponsive to IL-18 stimulation and maintain CD16 expression. However, the mechanism involved in this IL-18 mediated NK cell differentiation process is still not completely known. The TNF converting enzyme, ADAM17, has been implicated in the shedding of NK cell receptor CD16, and is therefore an interesting molecule of study for the mechanism of NK cell differentiation. The results of this study highlight the roles of both IL-18 and ADAM17 in the differentiation of NK cells into a functionally distinct “memory-like” NK helper cell subset and implicates a potential role of ADAM17 in the development of FcR- NK cells. Moreover, this study highlights the parallel that exists between NK cells and T cells, with both having the capacity to differentiate into adaptive cytolytic vs helper cell subsets. Overall, this underscores the need to continue to identify and study the causative mechanisms contributing to NK cell immune irregularities seen in PLWH. A better understanding of how these different NK cell populations arise naturally, how they can be induced, and their role in chronic HIV-1 infection and associated comorbidities can lead to more effective targeting of NK cells in HIV-1 comorbidity and remission studies
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
17 May 2024 |
| Date Type: |
Publication |
| Defense Date: |
10 April 2024 |
| Approval Date: |
17 May 2024 |
| Submission Date: |
16 April 2024 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
71 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Public Health > Infectious Diseases and Microbiology |
| Degree: |
MPH - Master of Public Health |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
NK cells, ADAM17, HIV, immune dysfunction, ADCC |
| Date Deposited: |
17 May 2024 17:56 |
| Last Modified: |
17 May 2024 17:56 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46136 |
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