Abstract
Recurrent viral diseases often occur after the viruses evade the hosts' immune system, by inducing exhaustion of antiviral T cells. In the present study, we found that functionally exhausted herpes simplex virus type 1 (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 (SYMP) patients with a history of numerous episodes of recurrent corneal herpetic disease. Similarly, following UV-B induced virus reactivation from latency the symptomatic wild-type (WT) 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 trigeminal ganglia (TG) and cornea. Moreover, a therapeutic blockade of LAG-3 immune checkpoint with antagonist antibodies combined with a therapeutic immunization with gB498−505 peptide immunodominant epitope of latently infected B6 mice significantly restored the quality and quantity of functional 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. In contrast to dysfunctional HSV-specific CD8+ T cells from 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. Thus, the LAG-3 pathway plays a fundamental role in ocular herpes T cell immunopathology and provides an important immune checkpoint target that can synergizes with T cell-based therapeutic vaccines against symptomatic recurrent ocular herpes.
Highlights
A staggering 3.72 billion individuals worldwide are infected with herpes simplex virus type 1 (HSV-1), a prevalent human viral pathogen [1,2,3]
Our findings suggest that: (i) Besides programmed death1 (PD-1), the LAG3 pathway plays a fundamental role in controlling herpes T cell immunity; (ii) Blockade of the lymphocyte activation gene-3 (LAG-3) pathway provides an important immune checkpoint that can synergize with T cellbased therapeutic herpes vaccines to protect against recurrent ocular herpes
The characteristics of the symptomatic (SYMP) and asymptomatic (ASYMP) study population used in this present study, with respect to gender, age, HLA-A∗02:01 frequency distribution, HSV-1/HSV-2 seropositivity and status of ocular and genital herpetic diseases are presented in Table 1 and detailed in the Materials and Methods section
Summary
A staggering 3.72 billion individuals worldwide are infected with herpes simplex virus type 1 (HSV-1), a prevalent human viral pathogen [1,2,3]. Blinding keratitis occurring from recurrent corneal herpetic disease results from the reactivation of latent virus from neurons of the TG, anterograde transportation to nerve termini, and re-infection of the cornea [8, 9]. HSV-specific CD8+ T cells can significantly reduce reactivation in TG explant from latently infected mice [5, 9], apparently by interfering with virus replication and spread following the initial molecular events of reactivation [5, 8, 9]. The virus appears to keep CD8+ T cells “in check” using among several mechanisms, functional impairment of T cells (i.e., exhaustion), which is usually the result of prolonged exposure of T cell to high levels of viral antigens, as occurs during productive chronic infections [12, 13]. Many viruses, including HSV-1, appear to reactivate from latency and sustain their productive infection by inducing functional exhaustion of antiviral CD8+ T cells [10, 12, 14,15,16,17]
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