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Dissertation
The cellular and signaling requirements of effector CD8⁺T cells during influenza A virus infection
Doctor of Philosophy (Ph.D.), Drexel University
Dec 2010
DOI:
https://doi.org/10.17918/00000687
Abstract
Experimental data from previous studies on T cell activation suggests that naive T cells are programmed at initiation in the lymph nodes by mature antigen presenting cells, to undergo further expansion in the absence of antigenic and costimulation signals (Signal II). Signal I involves the binding of antigen loaded MHC-I molecule on the surface APC with the T cell receptor on the surface of the naive T cell. Signal II is the interaction between costimulatory receptor such as CD28 with its ligand B7-1 and B7-2 on the surface of the stimulated APC. Activated naive T cells undergo cell division and become effector T cells possessing effector functions such as cytolytic activity and secretion of IFN[gamma]. Although much is known about the programmed division of activated naive T cells in the lymph nodes, it is not clear whether the effector T cells in the periphery are able to expand in the absence of signals I and II. We utilized a murine model of influenza A virus (IAV) infection to examine the effector CD8+ T cell responses in the lungs and found that at the effector phase, the virus-specific CD8+ T cells in the lungs do not strictly follow the tenets of programmed responses and require the presence of DCs, antigen and CD28 costimulation for their expansion and survival. Removal of DCs, cognate antigen or disruption of CD28 costimulation during the effector phase leads to a decreased anti-viral CD8+ T cell response in the lungs. The reduction in the virus-specific CD8 + T cells in the lungs is due to apoptosis of the effector CD8 + T in the absence of antigen and costimulation and is mediated by the pro-apoptotic molecule BIM. We have also observed that pro-survival cytokines such as IL-2 can rescue effector T cells in the absence of CD28 costimulation. The information from this study is important for designing vaccines against IAV and for understanding the impaired effector CD8+ T cell responses against viruses and tumors where DC maturation may be inhibited. This study will also help in understanding chronic infections which are characterized by the accumulation of CD28-/- CD8+ T cells.
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Details
- Title
- The cellular and signaling requirements of effector CD8⁺T cells during influenza A virus infection
- Creators
- Priyanka Duttagupta
- Contributors
- Peter D. Katsikis (Advisor)
- Awarding Institution
- Drexel University
- Degree Awarded
- Doctor of Philosophy (Ph.D.)
- Publisher
- Drexel University; Philadelphia, Pennsylvania
- Number of pages
- xvii, 167 pages
- Resource Type
- Dissertation
- Language
- English
- Academic Unit
- Microbiology and Immunology; College of Medicine; Drexel University
- Other Identifier
- 991014970336104721