Tissue-resident T cell derived cytokines eliminate herpes simplex virus-2-infected cells
Open Access
- 1 June 2020
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 130 (6), 2903-2919
- https://doi.org/10.1172/JCI132583
Abstract
The mechanisms underlying rapid elimination of herpes simplex virus-2 (HSV-2) in the human genital tract despite low CDEV and CD4(+) tissue-resident T cell (Trm cell) density are unknown. We analyzed shedding episodes during chronic HSV-2 infection; viral clearance always predominated within 24 hours of detection even when viral load exceeded 1 x10(2) HSV DNA copies, and surges in granzyme B and IFN-gamma occurred within the early hours after reactivation and correlated with local viral load. We next developed an agent-based mathematical model of an HSV-2 genital ulcer to integrate mechanistic observations of Trm cells in in situ proliferation, trafficking, cytolytic effects, and cytokine alarm signaling from murine studies with viral kinetics, histopathology, and lesion size data from humans. A sufficiently high density of HSV-2-specific Trm cells predicted rapid elimination of infected cells, but our data suggest that such Trm cell densities are relatively uncommon in infected tissues. At lower, more commonly observed Trm cell densities, Trm cells must initiate a rapidly diffusing, polyfunctional cytokine response with activation of bystander T cells in orderto eliminate a majority of infected cells and eradicate briskly spreading HSV-2 infection.Funding Information
- National Institute of Allergy and Infectious Diseases (P01 AI030731)
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (R01 AI121129)
This publication has 70 references indexed in Scilit:
- Immune surveillance by CD8αα+ skin-resident T cells in human herpes virus infectionNature, 2013
- Rapid localized spread and immunologic containment define Herpes simplex virus-2 reactivation in the human genital tracteLife, 2013
- Bystander-Activated Memory CD8 T Cells Control Early Pathogen Load in an Innate-like, NKG2D-Dependent MannerCell Reports, 2013
- Tissue-resident memory CD8 + T cells continuously patrol skin epithelia to quickly recognize local antigenProceedings of the National Academy of Sciences of the United States of America, 2012
- A vaccine strategy that protects against genital herpes by establishing local memory T cellsNature, 2012
- Cytotoxic immunological synapses do not restrict the action of interferon-γ to antigenic target cellsProceedings of the National Academy of Sciences of the United States of America, 2012
- Mucosal host immune response predicts the severity and duration of herpes simplex virus-2 genital tract shedding episodesProceedings of the National Academy of Sciences of the United States of America, 2010
- Persistence of HIV-1 receptor–positive cells after HSV-2 reactivation is a potential mechanism for increased HIV-1 acquisitionNature Medicine, 2009
- Memory T cells in nonlymphoid tissue that provide enhanced local immunity during infection with herpes simplex virusNature Immunology, 2009
- Reactivation of Genital Herpes Simplex Virus Type 2 Infection in Asymptomatic Seropositive PersonsThe New England Journal of Medicine, 2000