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

摘要

Herpes Simplex Virus 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 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 asymptomatic (ASYMP) and symptomatic (SYMP) individuals (with a documented history of numerous episodes of recurrent ocular herpetic disease). We report that, while SYMP and ASYMP individuals have similar frequencies of HSV-specific CD8⁺ T cells, the “naturally” protected ASYMP individuals have a significantly higher proportion of multi-functional HSV-specific effector memory CD8⁺ T cells (CD73⁺CD45RA^highCCR7^lowCD8⁺ TEMRA and CD73⁺CD45RA^lowCCR7^lowCD8⁺ TEM) as compared to SYMP individuals. Similar to humans, HSV-1 infected ASYMP B6 mice had frequent multi-functional HSV-specific CD73⁺CD8⁺ T cells in the cornea, as compared to SYMP mice. Moreover, in contrast to wild-type (WT) 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.