Lamens, Kristina
(2019)
Defining the role of CD4+ T cells during human metapneumovirus infection.
Master's Thesis, University of Pittsburgh.
(Unpublished)
This is the latest version of this item.
Abstract
Human metapneumovirus (HMPV) is a leading cause of respiratory tract infection in pediatric, elderly, and immunocompromised populations. Clearance of respiratory viruses like HMPV rely primarily on the destruction of infected cells by cytotoxic CD8+ T cells. However, signals provided by CD4+ helper T cells significantly impact the magnitude and effectiveness of CD8+ T cells. Despite HMPV being an important human pathogen, the role of CD4+ helper T cells in the immune response to HMPV is largely unknown. Using a C57BL/6 mouse model of acute infection, we identified an immunodominant CD4+ T cell epitope in the viral nucleoprotein and constructed the first MHC-II tetramer for HMPV. Analysis of pulmonary T cells revealed that virus-specific cells were most abundant on day 10 post-infection and were TH1-skewed. Additionally, virus-specific CD4+ T cells displayed phenotypic and functional markers of impairment, including inhibitory receptor co-expression and prolonged PD-1 upregulation. To determine the contribution of CD4+ T cells to the CD8+ T cell response, CD4+ T cells were antibody-depleted prior to HMPV infection. Depletion of CD4+ T cells led to delayed viral clearance and enhanced PD-1 expression on virus-specific CD8+ T cells. We also investigated the importance of CD40/CD40L signaling as a mechanism of CD4+ T cell help and demonstrate that either enhancing or blocking this pathway is detrimental in the context of HMPV infection. Further characterization of virus-specific CD4+ helper T cells, their regulation by PD-1, and their role in CD8+ T cell impairment will provide new insights that aid in the design of effective vaccines for HMPV.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
21 October 2019 |
| Date Type: |
Publication |
| Defense Date: |
1 October 2019 |
| Approval Date: |
21 October 2019 |
| Submission Date: |
4 October 2019 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
59 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Microbiology and Immunology |
| Degree: |
MS - Master of Science |
| Thesis Type: |
Master's Thesis |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
respiratory virus, HMPV, CD4+ T cells |
| Date Deposited: |
21 Oct 2019 15:22 |
| Last Modified: |
21 Oct 2021 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/37699 |
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