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Immunity and Immunopathogenesis to Herpesviruses

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Front. Immunol. | doi: 10.3389/fimmu.2018.02922

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

 LBACHIR BENMOHAMED1*,  Soumyabrata Roy1,  Pierre-Gregoire A. Coulon1, Ruchi Srivastava1, Hawa Vahed1,  Grace J. Kim1, Sager S. Walia1, Taikun Yamada1*, Mona A. Fouladi1 and Vincent T. Ly1
  • 1University of California, Irvine, United States

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 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.

Keywords: Herpes simple type 1, CD8 cells +, LAG-3, immune check point, recurrent, therapeutic, animal model, Humans

Received: 06 Oct 2018; Accepted: 28 Nov 2018.

Edited by:

Richard D. Dix, Georgia State University, United States

Reviewed by:

Deepak Shukla, University of Illinois at Chicago, United States
Homayon Ghiasi, Cedars-Sinai Medical Center, United States  

Copyright: © 2018 BENMOHAMED, Roy, Coulon, Srivastava, Vahed, Kim, Walia, Yamada, Fouladi and Ly. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Prof. LBACHIR BENMOHAMED, University of California, Irvine, Irvine, United States, Lbenmoha@uci.edu
Mr. Taikun Yamada, University of California, Irvine, Irvine, United States, taikuny@uci.edu