Tissue resident memory CD8 T cells augment innate immunity for tissue-wide antiviral protection

Abstract

Tissue-resident memory (TRM) CD8+ T cells provide effective, localized protection against pathogen re-encountering at barrier surfaces. During human herpes simplex virus 2 (HSV-2) infection, TRM CD8+ T cells persist at dermal-epidermal junction, interacting with basal keratinocytes and performing immune containment. The precise mechanism of how a few TRM CD8+ T cells convey broad tissue-wide protection is unclear. This study investigated the effects of TRM CD8+ T cells on tissue microenvironment by laser microdissecting and transcription profiling keratinocytes during human genital HSV-2 infection. In asymptomatic reactivation and lesion forming recurrences, keratinocytes exhibited a cell-intrinsic antiviral signature. Genes involved in RNA trafficking and protein translation were down-regulated, while a subset of interferon stimulated genes (ISGs) was elevated. The ISG expression was widely spread throughout the epidermis in the affected area. IFN-γ was expressed in TRM CD8+ T cells, but IFN-α and IFN-β were undetectable in keratinocytes and whole tissue. In primary cultured keratinocyte and fibroblast cells, pretreatment of IFN-γ delayed and restricted HSV gene expression at immediate-early stage of viral transcription. The inhibition on viral gene expression was dose-dependent and relied on IFN-γ receptor signaling. Thus, by harnessing cell-intrinsic innate immunity, TRM CD8+ T cells convey a tissue-wide antiviral protection in a non-cytolytic manner.