Immune surveillance by CD8αα+ skin-resident T cells in human herpes virus infection

Abstract

Summary Most herpes simplex virus 2 (HSV-2) reactivations in humans are subclinical and associated with rapid expansion and containment of virus. Previous studies have shown CD8+ T cells persist in genital skin and mucosa at the dermal-epidermal junction (DEJ), the portal of neuronal release of reactivating virus, for prolonged time periods after lesions are cleared1,2. The phenotype and function of this persistent CD8+ T-cell population remain unknown. Here, using cell type-specific laser capture microdissection, transcriptional profiling and T-cell receptor beta (TCRβ) genotyping on sequential genital skin biopsies, we show CD8αα+ T cells are the dominant resident population of DEJ CD8+ T cells that persist at the site of prior HSV-2 reactivation. CD8αα+ T cells located at the DEJ lack chemokine receptor expression required for lymphocyte egress and recirculation, express gene signatures of T-cell activation and antiviral activity, and produce cytolytic granules during clinical and virological quiescent time periods. Sequencing of the TCRβ chain repertoire revealed that the DEJ CD8αα+ T cells are oligoclonal with diverse usage of TCR VB genes, which differ from those commonly described for MAIT and NKT cells. Dominant clonotypes overlapped among multiple recurrence episodes over a period of two and a half years. Episodes of rapid asymptomatic HSV-2 containment were also associated with a high CD8 effector-to-target ratio and focal enrichment of CD8αα+ T cells. These studies indicate DEJ CD8αα+ T cells are tissue resident cells that appear to play a fundamental role in immune surveillance and in initial containment of HSV-2 reactivation in human peripheral tissue. Elicitation of CD8αα+ T cells might be a critical component for developing effective vaccines against skin and mucosal infections.

Biomarker evaluation of face transplant rejection: association of donor T cells with target cell injury

“…20 Such Trm cells also may respond to HSV infection, where the CD8 þ phenotype mediates epidermal involvement, and the CD4 þ subset is engaged in deeper dermal interactions. 39 The donor cells noted in the present study of facial allograft rejection express CD69, CD103 and CLA biomarkers, defining them as Trm cells. 35,[42][43][44] Their spatial association with sites of epithelial and endothelial injury strongly implicates donor T cells in the pathogenesis of rejection.…”

“…38 Today, skin is recognized as a rich repository of resident lymphocytes that provide protection by patrolling for pathogens and other noxious antigens. 20,39 In 2001, Hayday et al rekindled interest in T cells resident to the skin. 40 In 2003, Curry et al for the first time established the replicative potential of resident T cells exposed to variety of immunologic stimuli in healthy-appearing 'normal' human skin.…”

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

“…Moreover, brain-resident effector memory CD8 + T-cell populations after Vesicular Stomatitis Virus infection in mice were found to express high levels of PD-1 and CTLA-4 88 . At the same time, these resident T-cells often contain high levels of granzymes 89 . Thus, viral infections establish resident memory T-cell populations in organs repetitively targeted by similar pathogens to enable rapid pathogen control.…”

Evolving models of the immunopathogenesis of T cell–mediated drug allergy: The role of host, pathogens, and drug response

“…These cells are mostly CD3 + and, in humans, are likely to express CD8αα and CD69, and secrete cytotoxic molecules such as perforin and granzyme. 18,124 According to the heterologous immunity model (Figure 3a), the pathogenesis of a T-cell mediated ADR, considered over the course of an affected individual's lifetime, can be summarized as follows: 1) A prerequisite feature of each T-cell mediated ADR is carriage of the HLA risk allele; this is necessary but not sufficient for the reaction. 2) The subject acquires primary infection by HHV (or other pathogen).…”