July 2019
Volume 60, Issue 9
Open Access
ARVO Annual Meeting Abstract  |   July 2019
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
Author Affiliations & Notes
  • Lbachir BenMohamed
    Univ of California-Irvine, Irvine, California, United States
  • Soumyabrata Roy
    Univ of California-Irvine, Irvine, California, United States
  • Pierre-Gregoire A Coulon
    Univ of California-Irvine, Irvine, California, United States
  • Ruchi Srivastava
    Univ of California-Irvine, Irvine, California, United States
  • Footnotes
    Commercial Relationships   Lbachir BenMohamed, None; Soumyabrata Roy, None; Pierre-Gregoire Coulon, None; Ruchi Srivastava, None
  • Footnotes
    Support  This work is supported by Public Health Service Research R01 Grants EY026103, EY019896 and EY024618 from National Eye Institute (NEI) and R21 Grant AI110902 from National Institutes of allergy and Infectious Diseases (NIAID), by The Discovery Center for Eye Research (DCER) and by a Research to Prevent Blindness (RPB) grant
Investigative Ophthalmology & Visual Science July 2019, Vol.60, 4625. doi:
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      Lbachir BenMohamed, Soumyabrata Roy, Pierre-Gregoire A Coulon, Ruchi Srivastava; 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. Invest. Ophthalmol. Vis. Sci. 2019;60(9):4625.

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      © ARVO (1962-2015); The Authors (2016-present)

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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.

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