Dysfunctional Senescent Herpes Simplex Virus-Specific CD57⁺CD8⁺ T Cells Are Associated with Symptomatic Recurrent Ocular Herpes in Humans

Herpes simplex virus (HSV)-specific CD8⁺ T cells protect mice from herpes infection and disease. However, the phenotype and function of HSV-specific CD8⁺ T cells that play a key role in the "natural" protection seen in HSV-1-seropositive healthy asymptomatic (ASYMP) patients (who have never had clinical herpes disease) remain to be determined. We previously reported that symptomatic (SYMP) patients (who have frequent bouts of recurrent ocular herpes disease) had more undifferentiated and dysfunctional HSV-specific CD8⁺ T cells. In contrast, healthy ASYMP individuals maintained a significantly higher proportion of differentiated polyfunctional CD8⁺ T cells. Here, we report that HSV-specific CD8⁺ T cells from 10 SYMP patients, but not HSV-specific CD8⁺ T cells from 10 ASYMP patients, have phenotypic and functional characteristics of cellular senescence, including: (i) high frequency of senescent (CD57⁺) and exhausted (PD-1⁺) CD8⁺ T cells; (ii) late terminally differentiated (KLRG1⁺), non-proliferating CD8⁺ T cells; (iii) HSV-specific CD8⁺ T cells which decreased in number over time and were not homeostatically maintained, as indicated by a reduction in the number of CD127⁺CD8⁺ T cells; (iv) loss of the co-stimulatory molecule CD28 on HSV-specific CD8⁺ T cells; and (v) decreased production of effector molecules (granzyme B and perforin) by HSV-specific CD8⁺ T cells. Our findings provide insights into the role of senescence in HSV-specific CD8⁺ T cells in susceptibility to recurrent herpes and have implications for T-cell-based immunotherapeutic strategies against recurrent herpes in humans.