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Defining the role of CD4+ T cells during human metapneumovirus infection

Lamens, Kristina (2019) Defining the role of CD4+ T cells during human metapneumovirus infection. Master's Thesis, University of Pittsburgh. (Unpublished)

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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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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Lamens, Kristinakdl24@pitt.edukdl240000-0002-2582-8010
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairKane,
Committee MemberMcElroy,
Committee MemberHand,
Committee MemberAlcorn,
Thesis AdvisorWilliams,
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

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