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Expanding the functional CD8+ T cell repertoire reduces HSV-1 reactivation from latency in sensory ganglia

St. Leger, Anthony J (2012) Expanding the functional CD8+ T cell repertoire reduces HSV-1 reactivation from latency in sensory ganglia. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Following corneal infection, herpes simplex virus (HSV)-1 establishes latency in sensory neurons of the trigeminal ganglia (TG). In humans, spontaneous and recurrent reactivation of HSV-1 from latency has the potential to cause lesions on the gums (stomatitis), lips (cold sores, fever blisters), cornea (stromal keratitis), and brain (encephalitis). Latently infected neurons were once thought be largely ignored by the host immune system. Existing evidence shows that not only do HSV-specific CD8 T cells recognize latently infected neurons; they actively maintain viral latency using proinflammatory cytokines and lytic granules containing granzymes. The premise of this study further characterized the nature of the CD8 T cell response. Previous studies displayed that in the C57BL/6 mouse; CD8 T cells infiltrate the TG and become situated in direct apposition to infected neurons. It was known that 50 % of the CD8 T cells recognized the immunodominant epitope on glycoprotein B (gB) while the specificities of the remaining CD8 T cells were undefined. In this study, we observed that the non-gB CD8 T cell repertoire was confined to 18 epitopes on 11 viral proteins. During acute infection, these cells, similar to gB498-505-specific CD8 T cells, readily produce cytokines and release lytic granules upon stimulation. Conversely, during latency, even though these cells remain in the TG, they lose the ability to produce cytokines and release lytic granules upon stimulation suggesting functional compromise, unlike gB498-505-specific CD8 T cells. We show that the immunosuppressive cytokine, IL-10, preferentially suppresses the non-gB498-505-specific CD8 T cell population. Upon administration of an antibody against the IL-10 receptor, we see a dramatic increase in functional non-gB498-505-specific CD8 T cells without apparent effect in the gB498-505-specific CD8 T cell population. This increase in functional CD8 T cells leads to a 50% reduction in viral reactivation from latency suggesting the possibility of anti-IL10R as a treatment of recurrent reactivation of HSV-1 from latency.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
St. Leger, Anthony Jajs50@pitt.eduAJS50
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorHendricks, Robert Lhendricksrr@upmc.eduRLH13
Committee MemberKinchington, Paulkinch@pitt.eduKINCH
Committee MemberGaffen, Sarah Lsig65@pitt.eduSIG65
Committee MemberSalter, Russell Drds@pitt.eduRDS
Committee MemberChalasani, Geethagec12@pitt.eduGEC12
Date: 30 November 2012
Date Type: Publication
Defense Date: 19 September 2012
Approval Date: 30 November 2012
Submission Date: 28 November 2012
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 149
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Immunology, Virology, Ophthalmology
Date Deposited: 30 Nov 2012 19:09
Last Modified: 19 Dec 2016 14:40


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