PMID- 30619285 OWN - NLM STAT- MEDLINE DCOM- 20191025 LR - 20221207 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 9 DP - 2018 TI - 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. PG - 2922 LID - 10.3389/fimmu.2018.02922 [doi] LID - 2922 AB - 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. FAU - Roy, Soumyabrata AU - Roy S AD - Laboratory of Cellular and Molecular Immunology, School of Medicine, Gavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States. FAU - Coulon, Pierre-Gregoire AU - Coulon PG AD - Laboratory of Cellular and Molecular Immunology, School of Medicine, Gavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States. FAU - Srivastava, Ruchi AU - Srivastava R AD - Laboratory of Cellular and Molecular Immunology, School of Medicine, Gavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States. FAU - Vahed, Hawa AU - Vahed H AD - Laboratory of Cellular and Molecular Immunology, School of Medicine, Gavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States. FAU - Kim, Grace J AU - Kim GJ AD - Laboratory of Cellular and Molecular Immunology, School of Medicine, Gavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States. FAU - Walia, Sager S AU - Walia SS AD - Laboratory of Cellular and Molecular Immunology, School of Medicine, Gavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States. FAU - Yamada, Taikun AU - Yamada T AD - Laboratory of Cellular and Molecular Immunology, School of Medicine, Gavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States. FAU - Fouladi, Mona A AU - Fouladi MA AD - Laboratory of Cellular and Molecular Immunology, School of Medicine, Gavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States. FAU - Ly, Vincent T AU - Ly VT AD - Laboratory of Cellular and Molecular Immunology, School of Medicine, Gavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States. FAU - BenMohamed, Lbachir AU - BenMohamed L AD - Laboratory of Cellular and Molecular Immunology, School of Medicine, Gavin Herbert Eye Institute, University of California, Irvine, Irvine, CA, United States. AD - Department of Molecular Biology and Biochemistry, University of California, Irvine, Irvine, CA, United States. AD - Institute for Immunology, School of Medicine, University of California, Irvine, Irvine, CA, United States. LA - eng GR - R01 EY026103/EY/NEI NIH HHS/United States GR - R01 AI143348/AI/NIAID NIH HHS/United States GR - R01 AI158060/AI/NIAID NIH HHS/United States GR - R01 EY019896/EY/NEI NIH HHS/United States GR - R21 AI110902/AI/NIAID NIH HHS/United States GR - UL1 TR001414/TR/NCATS NIH HHS/United States GR - R21 AI143326/AI/NIAID NIH HHS/United States GR - R01 EY024618/EY/NEI NIH HHS/United States PT - Journal Article PT - Observational Study PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20181217 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - 0 (Antigens, CD) RN - 0 (Epitopes, T-Lymphocyte) RN - 0 (Herpes Simplex Virus Vaccines) RN - 0 (Immunodominant Epitopes) RN - 0 (Programmed Cell Death 1 Receptor) RN - 0 (Lymphocyte Activation Gene 3 Protein) SB - IM MH - Adult MH - Aged MH - Animals MH - Antigens, CD/genetics/*immunology MH - CD8-Positive T-Lymphocytes/*immunology MH - Cornea/immunology/metabolism/radiation effects/virology MH - Disease Models, Animal MH - Epitopes, T-Lymphocyte/immunology MH - Female MH - Herpes Simplex Virus Vaccines/*therapeutic use MH - Herpesvirus 1, Human/*immunology/radiation effects MH - Humans MH - Immunodominant Epitopes/immunology MH - Keratitis, Herpetic/immunology/*therapy/virology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Middle Aged MH - Programmed Cell Death 1 Receptor/immunology/metabolism MH - Recurrence MH - Ultraviolet Rays/adverse effects MH - Virus Shedding/radiation effects MH - Young Adult MH - Lymphocyte Activation Gene 3 Protein PMC - PMC6304367 OTO - NOTNLM OT - CD8+ T cells OT - LAG-3 OT - animal model OT - herpes simplex type 1 OT - humans OT - immune check point OT - recurrent OT - therapeutic EDAT- 2019/01/09 06:00 MHDA- 2019/10/28 06:00 PMCR- 2018/01/01 CRDT- 2019/01/09 06:00 PHST- 2018/10/06 00:00 [received] PHST- 2018/11/28 00:00 [accepted] PHST- 2019/01/09 06:00 [entrez] PHST- 2019/01/09 06:00 [pubmed] PHST- 2019/10/28 06:00 [medline] PHST- 2018/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2018.02922 [doi] PST - epublish SO - Front Immunol. 2018 Dec 17;9:2922. doi: 10.3389/fimmu.2018.02922. eCollection 2018.