Parks, Olivia B
(2024)
The role of age and complement in CD8+ T cell function during human metapneumovirus (HMPV) infection.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Human metapneumovirus (HMPV) is a leading cause of severe respiratory disease in young children <5yrs old, older adults >65yrs old, and the immunocompromised. HMPV immunity is incomplete with re-infections occurring throughout childhood and adulthood. Re-infections usually result in mild, self-resolving disease except in the elderly, who are at risk for severe disease and co-morbidities. The aged immune response to respiratory viruses such as HMPV is not fully understood. Aging studies have identified marked CD8+ T cell dysfunction due to cell-intrinsic epigenetic changes in gene expression and subsequent function. Thus, we hypothesized that age-related CD8+ T cell dysfunction contributes to severe respiratory disease in the aged host. We found that aged mice produced fewer HMPV tetramer+ CD8+ T cells, which had higher PD-1 expression and other inhibitory receptors and were less polyfunctional with decreased granzyme B. Previous studies have also identified an integral role of PD-1/L signaling in CD8+ T cell function in a young host. Blockade of PD-1/L signaling improves CD8+ T cell antiviral function in young mice. We further hypothesized that PD-1/L signaling was also critical to rejuvenate exhausted CD8+ T cells in the aged host. We found that removal of PD-1 improved granzyme B production and reduced the accumulation of cytotoxic tissue-resident memory CD8+ T cells in the aged host. In a concurrent study, we investigated other regulators of CD8+ T cell function during HMPV infection. Notably, we found that the complement protein, C1q, produced by inflammatory monocytes modulates CD8+ T cell antiviral function through the receptor, gC1qR. Taken together, this work explores the relationship between severe respiratory disease in an aged mouse model and CD8+ T cell function upon primary infection and re-challenge, the role of PD-1/L signaling in aged CD8+ T cell antiviral function, and identifies C1q as a novel regulator of CD8+ T cell function.
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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Unpublished |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: |
21 August 2024 |
| Date Type: |
Publication |
| Defense Date: |
8 January 2024 |
| Approval Date: |
21 August 2024 |
| Submission Date: |
14 January 2024 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
257 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Microbiology and Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
aging, CD8+ T cells, respiratory virus |
| Related URLs: |
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| Date Deposited: |
22 Aug 2024 03:50 |
| Last Modified: |
22 Aug 2024 03:50 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/45222 |
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