γδ T17 Cells Regulate the Acute Antiviral Response of NK Cells in HSV-1-Infected Corneas

P URPOSE . To determine whether gamma S T cells regulate natural killer (NK) cells in the herpes simplex virus 1 (HSV-1)-infected cornea. M ETHODS . CD57Bl/6 (wild-type [WT]), TCRS-/-, and IFN-gamma-/- mice were infected intracorneally with HSV-1. TCR-/- mice were treated with IL-17A at 24 hours post-infection (PI), and the WT mice received treatments of fingolimod (FTY720) and anti-IL-17A. At 48 hours PI, corneas were excised, and intracellular staining flow cytometry was performed, as well as multiplex analysis. Additionally, single-cell RNA sequencing (scRNAseq) was done to analyze the transcriptome of NK cells from WT and TCRS-/- mice. R ESULTS . In mice lacking gamma S T cells, there were significantly fewer NK cells following ocular HSV-1 infection. This reduction of NK cells corresponded with lower levels of cytokines and chemokines associated with the antiviral response. Furthermore, NK cells from WT mice had enriched IL-17A signaling compared to those from TCRS-/- mice. The NK cell response was partially rescued in TCRS-/- mice by administration of IL-17A. Correspondingly, the NK cell response could be blunted in WT mice by administration of anti-IL-17A. Finally, IFN-gamma-/- mice had significantly less IL-17A production compared to WT mice. C ONCLUSIONS . gamma S T17 cells promote NK cell accumulation in HSV-1-infected corneas. In turn, NK cells secrete IFN-gamma, which negatively regulates further IL-17A production by gamma S T cells.