Upregulation of Multiple CD8 + T Cell Exhaustion Pathways Is Associated with Recurrent Ocular Herpes Simplex Virus Type 1 Infection

A large proportion of the world's population harbors latent HSV type 1 (HSV-1). Cross-talk between antiviral CD8 T cells and HSV-1 appear to control latency/reactivation cycles. We found that compared with healthy asymptomatic individuals, in symptomatic (SYMP) patients, the CD8 T cells with th...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2020-07, Vol.205 (2), p.454-468
Main Authors: Coulon, Pierre-Grégoire, Roy, Soumyabrata, Prakash, Swayam, Srivastava, Ruchi, Dhanushkodi, Nisha, Salazar, Stephanie, Amezquita, Cassandra, Nguyen, Lan, Vahed, Hawa, Nguyen, Angela M, Warsi, Wasay R, Ye, Caitlin, Carlos-Cruz, Edgar A, Mai, Uyen T, BenMohamed, Lbachir
Format: Article
Language:English
Subjects:
Adult
Animals
Antibodies, Blocking - metabolism
Asymptomatic Diseases
CD8-Positive T-Lymphocytes - immunology
Cells, Cultured
Disease Progression
Eye - immunology
Eye - virology
Female
Herpes Simplex - immunology
Herpesvirus 1, Human - physiology
HLA-A2 Antigen - metabolism
Host-Pathogen Interactions
Humans
Male
Mice, Transgenic
Middle Aged
Programmed Cell Death 1 Receptor - immunology
Programmed Cell Death 1 Receptor - metabolism
Virus Activation
Virus Latency
Young Adult
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Summary:A large proportion of the world's population harbors latent HSV type 1 (HSV-1). Cross-talk between antiviral CD8 T cells and HSV-1 appear to control latency/reactivation cycles. We found that compared with healthy asymptomatic individuals, in symptomatic (SYMP) patients, the CD8 T cells with the same HLA-A*0201-restricted HSV-1 epitope specificities expressed multiple genes and proteins associated to major T cell exhaustion pathways and were dysfunctional. Blockade of immune checkpoints with anti-LAG-3 and anti-PD-1 antagonist mAbs synergistically restored the frequency and function of antiviral CD8 T cells, both 1) ex vivo, in SYMP individuals and SYMP HLA-A*0201 transgenic mice; and 2) in vivo in HSV-1-infected SYMP HLA-A*0201 transgenic mice. This was associated with a significant reduction in virus reactivation and recurrent ocular herpetic disease. These findings confirm antiviral CD8 T cell exhaustion during SYMP herpes infection and pave the way to targeting immune checkpoints to combat recurrent ocular herpes.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.2000131