A major challenge to combating ocular herpes simplex virus type 1 (HSV-1) infection lies in controlling the protective and immunopathological potential of the immune system. Numerous studies have shown that the immune system, especially CD8 T cells, plays an integral role in the establishment and maintenance of viral latency. In contrast, CD4 T cells mediate an immunoinflammatory response in the infected cornea termed herpes stromal keratitis (HSK) that leads to scarring and blindness. Here we address several hypotheses related to the role of CD4 T cells following ocular HSV-1 infection.
First, we asked if stimulation through the costimulatory pair CD134/OX40L is required for the activation of CD4 T cells within the infected cornea and subsequent inflammation. Our findings established that both CD134 and OX40L are expressed in the cornea during HSK. However, blocking CD134/OX40L interactions did not alleviate HSK. Our second hypothesis was that HSV-specific CD4 T cells are required to initiate HSK, but bystander activation becomes important during the later, chronic stages of disease. To address this hypothesis we isolated and cloned CD4 T cells from infected corneas, demonstrated their reactivity to viral antigens, and confirmed their capacity to mediate HSK in nude mice. These cells will be used in future studies to investigate the relative role of antigen-specific and bystander activated CD4 T cells in HSK. Next, we tested the hypothesis that while CD4 T cells are the primary mediators of inflammation in the cornea, CD8 T cells can also mediate inflammation in their absence. Our findings established that CD8 T cells can mediate HSK, but CD8 T cell-mediated HSK is transient and only induced when high doses of virus are used to infect the cornea.
We also tested our hypothesis that CD4 T cell help is required for the proper generation and maintenance of memory CD8 T cells at the site of viral latency. Our findings demonstrate that CD4 T cells control the contraction phase of the effector CD8 T cell response within the TG, the generation of CD8 memory precursors, and directly or indirectly influence viral genome burden within sensory neurons following ocular infection.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-06102005-130525 |
| Date | 25 July 2005 |
| Creators | Lepisto, Andrew John |
| Contributors | Paul R. Kinchington, JoAnne L. Flynn, Olivera J. Finn, Robert L. Hendricks, Anuradha Ray |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-06102005-130525/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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