Abstract
The nature of antiviral CD8+ T cells associated with protective and pathogenic herpes simplex virus type 1 (HSV-1) infections remains unclear. We compared the transcriptome, phenotype, and function of memory CD8+ T cells, sharing the same HSV-1 epitope-specificities, from infected HLA-A*0201 positive symptomatic (SYMP) vs. asymptomatic (ASYMP) individuals and HLA-A*0201 transgenic rabbits. Compared to higher frequencies of multifunctional effector memory CD8+ TEM cells in ASYMP individuals, the SYMP individuals presented dysfunctional CD8+ TEM cells, expressing major exhaustion pathways. Compared to protected ASYMP HLA transgenic rabbits, the trigeminal ganglia of non-protected SYMP HLA transgenic rabbits had higher frequencies of dysfunctional tissue-resident CD8+ TRM cells. Moreover, blockade of T cell exhaustion pathways restored the function of CD8+ T cells, reduced virus reactivation, and diminished recurrent disease in HLA transgenic rabbits. These findings reveal unique molecular signatures of protective CD8+ T cells and pave the way for T-cell-based immunotherapy to combat recurrent ocular herpes.
Highlights
The nature of antiviral C D8+ T cells associated with protective and pathogenic herpes simplex virus type 1 (HSV-1) infections remains unclear
Blood-derived CD8+ T cells, specific to two human leukocyte antigens (HLA)-A*0201-restricted HSV-1 epitopes selected from the membrane glycoprotein B (gB561–569), and tegument protein VP11/12 (VP11–12702–710), were sorted (Supplementary Fig. S2) by fluorescence-activated cell sorting (FACS) from: (1) HLA-A*0201positive SYMP individuals that exhibit frequent and severe recurrent ocular herpetic disease (n = 2); and (2) HLA-A*0201-positive ASYMP individuals that never have any recurrent herpetic disease despite being seropositive (n = 2) (Fig. 1a)
A bulk RNA sequencing specific heatmap confirmed the significant upregulation of cell adhesion molecule (CAM) pathway-specific gene expression (i.e., CEACAM8, NRCAM, LAMA1, SELE, and NLGN3) and T cell exhaustion genes (i.e., PD-1, LAG-3, PSGL-1, CTLA-4, TIM3, and TIGIT) in HSV-specific CD8+ T cells from the SYMP patients compared to HSV-specific CD8+ T cells from the ASYMP individuals (Fig. 1e)
Summary
The nature of antiviral C D8+ T cells associated with protective and pathogenic herpes simplex virus type 1 (HSV-1) infections remains unclear. Phenotype, and function of memory C D8+ T cells, sharing the same HSV-1 epitope-specificities, from infected HLA-A*0201 positive symptomatic (SYMP) vs asymptomatic (ASYMP) individuals and HLA-A*0201 transgenic rabbits. Blockade of T cell exhaustion pathways restored the function of C D8+ T cells, reduced virus reactivation, and diminished recurrent disease in HLA transgenic rabbits These findings reveal unique molecular signatures of protective C D8+ T cells and pave the way for T-cell-based immunotherapy to combat recurrent ocular herpes. We performed bulk and scRNASeq transcriptomic, phenotypic and functional analyses of blood and tissue-resident CD8+ T cells, specific to multiple and same HLA-A*0201-restricted HSV-1 epitopes from HSV-1 infected symptomatic and asymptomatic patients and from our HLA-A*0201 transgenic rabbit (HLA Tg rabbit) model of recurrent ocular h erpes[18,28,31,35]. The findings from this study pave the way for T-cell-based immunotherapy to combat recurrent ocular herpes in humans
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