Phenotypic and Functional Signatures of Herpes Simplex Virus–Specific Effector Memory CD73+CD45RAhighCCR7lowCD8+ TEMRA and CD73+CD45RAlowCCR7lowCD8+ TEM Cells Are Associated with Asymptomatic Ocular Herpes

HSV type 1 (HSV-1)-specific CD8 + T cells protect from herpes infection and disease. However, the nature of protective CD8 + T cells in HSV-1 seropositive healthy asymptomatic (ASYMP) individuals (with no history of clinical herpes disease) remains to be determined. In this study, we compared the phenotype and function of HSV-specific CD8 + T cells from HLA-A*02:01-positive ASYMP and symptomatic (SYMP) individuals (with a documented history of numerous episodes of recurrent ocular herpetic disease). We report that although SYMP and ASYMP individuals have similar frequencies of HSV-specific CD8 + T cells, the "naturally" protected ASYMP individuals have a significantly higher proportion of multifunctional HSV-specific effector memory CD8 + T cells (CD73 + CD45RA high CCR7 low CD8 + effector memory RA (T EMRA ) and CD73 + CD45RA low CCR7 low CD8 + effector memory (T EM ) as compared with SYMP individuals. Similar to humans, HSV-1-infected ASYMP B6 mice had frequent multifunctional HSV-specific CD73 + CD8 + T cells in the cornea, as compared with SYMP mice. Moreover, in contrast to wild type B6, CD73 -/- deficient mice infected ocularly with HSV-1 developed more recurrent corneal herpetic infection and disease. This was associated with less functional CD8 + T cells in the cornea and trigeminal ganglia, the sites of acute and latent infection. The phenotypic and functional characteristics of HSV-specific circulating and in situ CD73 + CD8 + T cells, demonstrated in both ASYMP humans and mice, suggest a positive role for effector memory CD8 + T cells expressing the CD73 costimulatory molecule in the protection against ocular herpes infection and disease. These findings are important for the development of safe and effective T cell-based herpes immunotherapy.