Tissue-Resident-Memory CD8+ T Cells Bridge Innate Immune Responses in Neighboring Epithelial Cells to Control Human Genital Herpes.

Tao Peng,Kurt Diem,Erik D Layton,David M Koelle,Alvason Li,Jia Zhu,David M Knipe,Yon Hwangbo,Anna Wald,Alexis Klock,Lawrence Corey,Keith R Jerome,Lei Jin,Christine Johnston,Khamsone Phasouk,Lichen Jing,Sijie Sun,Meei‐Li Huang ,Kerry J Laing ,Catherine Sodroski ,Amalia Magaret ,Max E Mertens

doi:10.3389/fimmu.2021.735643

Abstract

Tissue-resident-memory T cells (TRM) populate the body’s barrier surfaces, functioning as frontline responders against reencountered pathogens. Understanding of the mechanisms by which CD8TRM achieve effective immune protection remains incomplete in a naturally recurring human disease. Using laser capture microdissection and transcriptional profiling, we investigate the impact of CD8TRM on the tissue microenvironment in skin biopsies sequentially obtained from a clinical cohort of diverse disease expression during herpes simplex virus 2 (HSV-2) reactivation. Epithelial cells neighboring CD8TRM display elevated and widespread innate and cell-intrinsic antiviral signature expression, largely related to IFNG expression. Detailed evaluation via T-cell receptor reconstruction confirms that CD8TRM recognize viral-infected cells at the specific HSV-2 peptide/HLA level. The hierarchical pattern of core IFN-γ signature expression is well-conserved in normal human skin across various anatomic sites, while elevation of IFI16, TRIM 22, IFITM2, IFITM3, MX1, MX2, STAT1, IRF7, ISG15, IFI44, CXCL10 and CCL5 expression is associated with HSV-2-affected asymptomatic tissue. In primary human cells, IFN-γ pretreatment reduces gene transcription at the immediate-early stage of virus lifecycle, enhances IFI16 restriction of wild-type HSV-2 replication and renders favorable kinetics for host protection. Thus, the adaptive immune response through antigen-specific recognition instructs innate and cell-intrinsic antiviral machinery to control herpes reactivation, a reversal of the canonical thinking of innate activating adaptive immunity in primary infection. Communication from CD8TRM to surrounding epithelial cells to activate broad innate resistance might be critical in restraining various viral diseases.

Highlights

During primary infection by a microbe, the host innate immune mechanisms provide the initial recognition of pathogenassociated molecular patterns and trigger off signaling pathways that help to control the pathogen and activate adaptive immune mechanisms [1]
Individual basal keratinocytes were microdissected in the vicinity of dermal-epidermal junction (DEJ) CD8+ TRM (CD8TRM) from skin tissue obtained at a post-healing site of herpes simplex virus (HSV)-2 recurrence as well as from control arm skin of the same individuals (n = 5) (Figure 1B, Supplementary Figure 1 and Table 1)
Among the annotated interferon stimulated genes (ISG), IFITM1, IFITM2, IFIT2, IFIT27, IFIT44, IFIT44L, OAS1, OAS2, OAS3, OASL, GBP1, GBP4, IFI6, Interferon gamma-inducible protein 16 (IFI16), IFI27 and IFI35 were up-regulated in keratinocytes from sites of prior HSV-2 recurrence as well as from active genital herpes lesions (Figure 1E), while GBP5, GBP7 and IFIT3 were elevated only in keratinocytes from lesion tissues

Summary

Introduction

During primary infection by a microbe, the host innate immune mechanisms provide the initial recognition of pathogenassociated molecular patterns and trigger off signaling pathways that help to control the pathogen and activate adaptive immune mechanisms [1]. The adaptive immune mechanisms provide a lasting antigen-specific immunity that controls the pathogen upon re-infection or recurrent infection. Recent evidence indicates that tissue-residentmemory T cells (TRM) infiltrate the infection site and persist in tissue for prolonged time periods, offering local protection in a timely and effective manner against pathogens reencountered at barrier surfaces [2,3,4,5,6,7,8,9,10,11]. Human herpes simplex virus (HSV) infection is a recurrent chronic disease, where latency and reactivation could occur over a large anatomic space involving the peripheral nervous system and the body’s barrier surface, including skin and oral/genital mucosa [13]. The mechanistic insights of how human hosts coordinate such rapid and widespread protection are yet to be elucidated

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Results

Conclusion