HSV-1 establishes latency in sensory neurons of the trigeminal ganglia (TG) following corneal infection. The concept that latently infected neurons are ignored by the host immune response has given way to the notion that CD8 T cells maintained in the TG monitor infected neurons thereby subverting reactivation. The tendency of HSV-1 to periodically reactivate in humans and mediate recurrent disease is associated with significant morbidity. A desire to understand the complex interactions of this pathogen, the neurons that harbor it, and the immune system that monitors latency define this study. Two populations of CD8 T cells rapidly infiltrate the TG coincident with resolution of replicating virus and juxtapose with neurons for the life of the mouse. One population recognizes the immunodominant glycoprotein B (gB) epitope while the other does not (gB-nonspecific). We establish that the homeostatic cytokine IL-15 does not contribute to the maintenance of gB-specific or gB-nonspecific CD8 T cells within the TG during latency. However, IL-15 is crucial for the regulation of gB-specific memory CD8 T cells in noninfected tissues. These findings led us to question whether gB-nonspecific CD8 T cells are important in the HSV-1 response. We demonstrate that gB-nonspecific CD8 T cells upregulate the effector molecule granzyme B, and produce IFNã and proliferate in response to HSV-1-infected but not gB-transfected targets. This data conclusively shows that gB-nonspecific CD8 T cells in the infected TG are HSV-1 specific. This population is also capable of preventing reactivation following explant of latent TG. Contrary to their gB-specific CD8 counterparts, gB-nonspecific CD8 T cells have a reduced capacity to produce IFNã during latency and this reduction in function is associated with increased expression of PD-1. Surprisingly, blockade of PD-L1 did not rescue effector function yet increased the viral burden during latency. We show that a population of neurons expressing PD-L1 contains an enriched reservoir of HSV-1 latency that is highly prone to reactivate.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-08132008-110945 |
| Date | 14 August 2008 |
| Creators | Sheridan, Brian Scott |
| Contributors | JoAnne L. Flynn, Ph.D., Robert L. Hendricks, Ph.D., Jay K. Kolls, M.D., J. Patrick Card, Ph.D., Penelope A. Morel, M.D. |
| 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-08132008-110945/ |
| 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. |
Page generated in 0.0805 seconds