Jeon, Sohyun
(2014)
The role of programmed death ligand-1 (PD-L1/B7-H1) in regulating the immune responses against herpes simplex virus-1 (HSV-1).
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Herpes simplex virus type 1 (HSV)-specific CD8+ T cells provide immunosurveillance of trigeminal ganglion (TG) neurons that harbor latent HSV-1 and prevent viral reactivation. Recurrent reactivations of HSV-1 from latency in the TG can result in severe corneal immunopathology and progressive scarring, leading to a blinding disease called Herpetic Stromal Keratitis. Therefore it is of significant clinical relevance to develop immunotherapies that are designed to boost the immune responses that prevent or reduce the frequency of HSV-1 reactivations. Programmed Death-1 (PD-1) is an inhibitory receptor that is expressed on many types of activated immune cells and regulates their cytokine production and numbers, with high levels of PD-1 inducing apoptosis and low expression inhibiting proliferation. Our goal was to investigate the role of a PD-1 ligand, PD-L1/B7-H1, during HSV-1 infection, and test whether blocking PD-L1 will enhance the innate immune response that clears the initial viral infection, and the adaptive immune response that prevents reactivation from latency. We used a mouse model of HSV-1 infection in which virus infection of the corneal epithelium leads to formation of a lesion; and simultaneous transmission of the virus to the TG results in establishment of HSV-1 latency in a portion of TG neurons. We found that PD-L1 was expressed on HSV-1- infected corneal epithelial cells during acute HSV-1 infection and was preferentially up- regulated by IFN-γ on HSV-1-infected neurons during latency. Using B7-H1/PD-L1-/- mice during acute HSV-1 infection, we found that 1) PD-L1 expressed on corneal epithelium and bone marrow-derived CD45+ cells in the cornea inhibits efficient recruitment of Gr-1+ cells (monocytes/neutrophils) by suppressing chemokine production, 2) PD-L1 expressed on corneal epithelium inhibits γδ T cell infiltration into the infected cornea, and 3) PD-L1 promotes proper DC maturation during T cell priming in the draining lymph nodes. During latent HSV-1 infection, PD-L1 expressed on TG neurons inhibits the survival but not proliferation and cytokine production of TG-resident subdominant CD8+ T cells. B7-H1-/- mice had an enlarged population of PD-1high subdominant CD8+ T cells that did not provide enhanced protection from HSV-1 reactivation, suggesting that PD-L1 blockade may not be an attractive option as immunotherapy against HSK.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
20 March 2014 |
| Date Type: |
Publication |
| Defense Date: |
11 December 2013 |
| Approval Date: |
20 March 2014 |
| Submission Date: |
20 March 2014 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
122 |
| 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, Ophthalmology, PD-1, PD-L1, Immune regulation, Immunotherapy, HSV-1 ocular infection, Inhibitory receptors |
| Date Deposited: |
20 Mar 2014 17:43 |
| Last Modified: |
19 Dec 2016 14:41 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/20775 |
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