Stress-induced glucocorticoids at the earliest stages of herpes simplex virus-1 infection suppress subsequent antiviral immunity, implicating impaired dendritic cell function

Michael D. Elftman, John T. Hunzeker, Jennifer C. Mellinger, Robert H. Bonneau, Christopher C. Norbury, Mary E. Truckenmiller

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

The systemic elevation of psychological stress-induced glucocorticoids strongly suppresses CD8+ Tcell immune responses resulting in diminished antiviral immunity. However, the specific cellular targets of stress/glucocorticoids, the timing of exposure, the chronology of immunological events, and the underlying mechanisms of this impairment are incompletely understood. In this study, we address each of these questions in the context of a murine cutaneous HSVinfection.We show that exposure to stress or corticosterone in only the earliest stages of an HSV-1 infection is sufficient to suppress, in a glucocorticoid receptor-dependent manner, the subsequent antiviral immune response after stress/corticosterone has been terminated. This suppression resulted in early onset and delayed resolution of herpetic lesions, reduced viral clearance at the site of infection and draining popliteal lymph nodes (PLNs), and impaired functions of HSV-specific CD8+ T cells in PLNs, including granzyme B and IFN-γ production and the ability to degranulate. In knockout mice lacking glucocorticoid receptors only in T cells, we show that these impaired CD8+ T cell functions are not due to direct effects of stress/corticosterone on the T cells, but the ability of PLN-derived dendritic cells to prime HSV-1-specific CD8+ T cells is functionally impaired. These findings highlight the susceptibility of critical early events in the generation of an antiviral immune response to neuroendocrine modulation and implicate dendritic cells as targets of stress/glucocorticoids in vivo. These findings also provide insight into the mechanisms by which the clinical use of glucocorticoids contributes to altered immune responses in patients with viral infections or tumors.

Original languageEnglish (US)
Pages (from-to)1867-1875
Number of pages9
JournalJournal of Immunology
Volume184
Issue number4
DOIs
StatePublished - Feb 15 2010

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