Unique molecular signatures of antiviral memory CD8⁺ T cells associated with asymptomatic recurrent ocular herpes

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⁺ T_EM cells in ASYMP individuals, the SYMP individuals presented dysfunctional CD8⁺ T_EM 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⁺ T_RM 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.