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Blockade of LAG-3 Immune Checkpoint Combined With Therapeutic Vaccination Restore the Function of Tissue-Resident Anti-viral CD8⁺ T Cells and Protect Against Recurrent Ocular Herpes Simplex Infection and Disease.

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 gB_498-505 peptide immunodominant epitope of latently infected B6 mice significantly restored the quality and quantity of functional HSV-1 gB_498-505 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.

SUBMITTER: Roy S

PROVIDER: S-EPMC6304367 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Blockade of LAG-3 Immune Checkpoint Combined With Therapeutic Vaccination Restore the Function of Tissue-Resident Anti-viral CD8<sup>+</sup> T Cells and Protect Against Recurrent Ocular Herpes Simplex Infection and Disease.

Roy Soumyabrata S Coulon Pierre-Grégoire PG Srivastava Ruchi R Vahed Hawa H Kim Grace J GJ Walia Sager S SS Yamada Taikun T Fouladi Mona A MA Ly Vincent T VT BenMohamed Lbachir L

Frontiers in immunology 20181217

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<sup>+</sup> 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 herpeti ...[more]

PMID: 30619285

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Project description:While the role of CD8+ T cells in the control of herpes simplex virus 1 (HSV-1) infection and disease is gaining wider acceptance, a direct involvement of effector CD4+ T cells in this protection and the phenotype and function of HSV-specific human CD4+ T cell epitopes remain to be fully elucidated. In the present study, we report that several epitopes from the HSV-1 virion tegument protein (VP11/12) encoded by UL46 are targeted by CD4+ T cells from HSV-seropositive asymptomatic individuals (who, despite being infected, never develop any recurrent herpetic disease). Among these, we identified two immunodominant effector memory CD4+ TEM cell epitopes, amino acids (aa) 129 to 143 of VP11/12 (VP11/12129-143) and VP11/12483-497, using in silico, in vitro, and in vivo approaches based on the following: (i) a combination of the TEPITOPE algorithm and PepScan library scanning of the entire 718 aa of HSV-1 VP11/12 sequence; (ii) an in silico peptide-protein docking analysis and in vitro binding assay that identify epitopes with high affinity to soluble HLA-DRB1 molecules; and (iii) an ELISpot assay and intracellular detection of gamma interferon (IFN-γ), CD107a/b degranulation, and CD4+ T cell carboxyfluorescein succinimidyl ester (CFSE) proliferation assays. We demonstrated that native VP11/12129-143 and VP11/12483-497 epitopes presented by HSV-1-infected HLA-DR-positive target cells were recognized mainly by effector memory CD4+ TEM cells while being less targeted by FOXP3+ CD4+ CD25+ regulatory T cells. Furthermore, immunization of HLA-DR transgenic mice with a mixture of the two immunodominant human VP11/12 CD4+ TEM cell epitopes, but not with cryptic epitopes, induced HSV-specific polyfunctional IFN-γ-producing CD107ab+ CD4+ T cells associated with protective immunity against ocular herpes infection and disease.IMPORTANCE We report that naturally protected HSV-1-seropositive asymptomatic individuals develop a higher frequency of antiviral effector memory CD4+ TEM cells specific to two immunodominant epitopes derived from the HSV-1 tegument protein VP11/12. Immunization of HLA-DR transgenic mice with a mixture of these two immunodominant CD4+ T cell epitopes induced a robust antiviral CD4+ T cell response in the cornea that was associated with protective immunity against ocular herpes. The emerging concept of developing an asymptomatic herpes vaccine that would boost effector memory CD4+ and CD8+ TEM cell responses is discussed.

Project description:Herpes simplex virus 1 (HSV-1) causes a lifelong infection of neurons that innervate barrier sites like the skin and mucosal surfaces like the eye. After primary infection of the cornea, the virus enters latency within the trigeminal ganglion (TG), from which it can reactivate throughout the life of the host. Viral latency is maintained, in part, by virus-specific CD8+ T cells that nonlethally interact with infected neurons. When CD8+ T cell responses are inhibited, HSV-1 can reactivate, and these recurrent reactivation events can lead to blinding scarring of the cornea. In the C57BL/6 mouse, CD8+ T cells specific for the immunodominant epitope from glycoprotein B maintain functionality throughout latency, while CD8+ T cells specific for subdominant epitopes undergo functional impairment that is associated with the expression of the inhibitory checkpoint molecule programmed death 1 (PD-1). Here, we investigate the checkpoint molecule T cell immunoglobulin and mucin domain-containing 3 (Tim-3), which has traditionally been associated with CD8+ T cell exhaustion. Unexpectedly, we found that Tim-3 was preferentially expressed on highly functional ganglionic CD8+ T cells during acute and latent HSV-1 infection. This, paired with data that show that Tim-3 expression on CD8+ T cells in the latently infected TG is influenced by viral gene expression, suggests that Tim-3 is an indicator of recent T cell stimulation, rather than functional compromise, in this model. We conclude that Tim-3 expression is not sufficient to define functional compromise during latency; however, it may be useful in identifying activated cells within the TG during HSV-1 infection.IMPORTANCE Without an effective means of eliminating HSV-1 from latently infected neurons, efforts to control the virus have centered on preventing viral reactivation from latency. Virus-specific CD8+ T cells within the infected TG have been shown to play a crucial role in inhibiting viral reactivation, and with a portion of these cells exhibiting functional impairment, checkpoint molecule immunotherapies have presented a potential solution to enhancing the antiviral response of these cells. In pursuing this potential treatment strategy, we found that Tim-3 (often associated with CD8+ T cell functional exhaustion) is not upregulated on impaired cells but instead is upregulated on highly functional cells that have recently received antigenic stimulation. These findings support a role for Tim-3 as a marker of activation rather than exhaustion in this model, and we provide additional evidence for the hypothesis that there is persistent viral gene expression in the HSV-1 latently infected TG.

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Blockade of LAG-3 Immune Checkpoint Combined With Therapeutic Vaccination Restore the Function of Tissue-Resident Anti-viral CD8⁺ T Cells and Protect Against Recurrent Ocular Herpes Simplex Infection and Disease.

Publications

Blockade of LAG-3 Immune Checkpoint Combined With Therapeutic Vaccination Restore the Function of Tissue-Resident Anti-viral CD8<sup>+</sup> T Cells and Protect Against Recurrent Ocular Herpes Simplex Infection and Disease.

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Blockade of LAG-3 Immune Checkpoint Combined With Therapeutic Vaccination Restore the Function of Tissue-Resident Anti-viral CD8+ T Cells and Protect Against Recurrent Ocular Herpes Simplex Infection and Disease.

Publications

Blockade of LAG-3 Immune Checkpoint Combined With Therapeutic Vaccination Restore the Function of Tissue-Resident Anti-viral CD8<sup>+</sup> T Cells and Protect Against Recurrent Ocular Herpes Simplex Infection and Disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Blockade of LAG-3 Immune Checkpoint Combined With Therapeutic Vaccination Restore the Function of Tissue-Resident Anti-viral CD8⁺ T Cells and Protect Against Recurrent Ocular Herpes Simplex Infection and Disease.