Abstract
Purpose :
A staggering 3.72 billion individuals worldwide are infected with herpes simplex virus type 1 (HSV-1), a prevalent human viral pathogen. The recurrent corneal herpetic disease occurs after the HSV-1 evades the hosts’ immune system, by inducing exhaustion of antiviral T cells. The mechanisms of T cell exhaustion during recurrent ocular herpes remain to be fully elucidated.
Methods :
In the present study, we: (i) compared phenotypic and functional exhaustion of peripheral blood-derived HSV-specific CD8+ T cells from HSV-1 infected asymptomatic individuals and symptomatic ocular herpes patients, with a history of numerous episodes of recurrent corneal herpetic disease; and (ii) study phenotypic and functional exhaustion of HSV-specific CD8+ T cells that resides in infected cornea and trigeminal ganglia (TG), using our established mouse model of recurrent ocular herpes.
Results :
We found that functionally exhausted HSV-1-specific CD8+ T cells, with elevated expression of lymphocyte activation gene-3 (LAG-3), an immune checkpoint receptor that promotes T cell exhaustion, were frequent in symptomatic patients. Similarly, following UV-B induced virus reactivation from latency the symptomatic B6 mice that developed increase virus shedding and severe recurrent corneal herpetic disease had more exhausted HSV-specific LAG-3+CD8+ T cells in both TG and cornea. In contrast to dysfunctional HSV-specific CD8+ T cells from wild-type (WT) B6 mice, more functional HSV-specific CD8+ T cells were detected in LAG-3-/- deficient mice and were associated with less UV-B induced recurrent corneal herpetic disease. Moreover, a therapeutic blockade of the LAG-3 immune checkpoint with antagonist antibodies combined with a therapeutic immunization with gB498-505 peptide immunodominant epitope of latently infected WT B6 mice significantly restored the quality and quantity of HSV-1 gB498-505 specific CD8+ T cells in both TG and cornea and protected against UV-B induced recurrent corneal herpes infection and disease.
Conclusions :
The LAG-3 pathway plays a fundamental role in ocular herpes T cell immunopathology and provides an important immune checkpoint target that can synergize with T cell-based therapeutic vaccines against symptomatic recurrent ocular herpes.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.