Virus-specific CD8+ T cells accumulate near sensory nerve endings in genital skin during subclinical HSV-2 reactivation

TLDR

Cytotoxic CD8+ T cells are essential for controlling HSV infection, yet their spatiotemporal dynamics during lesion evolution and post‑resolution surveillance remain poorly understood. The study aimed to map the in vivo localization of HSV‑2–specific CD8+ T cells across acute, resolving, and healed stages of genital skin reactivation. This was achieved by using quantum dot–conjugated peptide–MHC multimers to visualize these cells in sequential biopsies. During acute HSV‑2 reactivation, functionally active CD8+ T cells infiltrate the lesion site, and even after complete healing and reepithelialization, HSV‑specific CD8+ T cells remain for over two months at the dermal‑epidermal junction adjacent to nerve endings, with viral DNA reappearing in clinically normal skin in two of six subjects accompanied by increased CD8+ T cells, demonstrating that persistent virus‑specific CD8+ T cells modulate reactivation frequency and clinical course.

Abstract

Cytotoxic CD8+ T cells play a critical role in controlling herpes simplex virus (HSV) infection and reactivation. However, little is known about the spatiotemporal dynamics of CD8+ T cells during HSV lesion evolution or about their involvement in immune surveillance after lesion resolution. Using quantum dot–conjugated peptide–major histocompatibility complex multimers, we investigated the in vivo localization of HSV-2–specific CD8+ T cells in sequential biopsies of human genital skin during acute, resolving, and healed stages of HSV-2 reactivation. Our studies revealed that functionally active CD8+ T cells selectively infiltrated to the site of viral reactivation. After lesion healing in concert with complete reepithelialization and loss of HSV DNA from skin biopsies, HSV-2–specific CD8+ T cells persisted for more than two months at the dermal–epidermal junction, adjacent to peripheral nerve endings. In two out of the six sequentially studied individuals, HSV-2 DNA reappeared in clinically and histologically normal–appearing skin. Detection of viral DNA was accompanied by increased numbers of both HSV-specific and total CD8+ T cells in the dermis. These findings indicate that the frequency and clinical course of HSV-2 reactivation in humans is influenced by virus-specific CD8+ T cells that persist in peripheral mucosa and genital skin after resolution of herpes lesions.