Abstract
We investigated the influence of a transient treatment of corticosteroid on CD8+ T cells during herpesvirus infection. Dexamethasone, a synthetic corticosteroid, induced apoptosis of naïve and memory CD8+ T cells but virus-specific effector cells were spared. CD8+ T cell susceptibility was directly correlated with the expression of nr3c1. Both α-(HSV1) and γ-(MHV68) herpesvirus infection expanded CD8+ T cells down regulated nr3c1 indicating corticosteroid-mediated effects were not limited to one pathogen or the specific clonotype. Dexamethasone compromised anti-viral immunity to subsequent infections, likely through reductions in the naïve cell pool. Dexamethasone augmented the function and inflammatory tissue homing potential of effector cells via upregulation of CXCR3. Accordingly, an antibody neutralization of CXCR3 diminished dexamethasone-induced migration of CD8+ T cells to tissues resulting in increased virus burden. Our study therefore suggests that even a transient corticosteroid therapy influences both ongoing CD8+ T cell responses as well as the size of the naïve and memory repertoire.
Highlights
Glucocorticoids cause immunosuppression and are commonly used to ameliorate inflammation resulting from infections, autoimmune diseases, leukemia as well as during transplantation procedures to avoid graft rejection [1,2,3]
We investigated the influence of such a transient therapy on differentiation program of virus-specific CD8+ T cells in HSV1 infected mice
We measured the frequencies and total number of cytokine producing CD8+ T cells responding to the immunodominant H-2Kb restricted gB498−505-(SSIEFARL) peptide of HSV1, using intracellular cytokine staining (ICCS) assays and essentially similar results were obtained for IFN-γ producing CD8+ T cells as well as its per cell basis expression (Figures 1G–J)
Summary
Glucocorticoids cause immunosuppression and are commonly used to ameliorate inflammation resulting from infections, autoimmune diseases, leukemia as well as during transplantation procedures to avoid graft rejection [1,2,3]. Synthetic analogs of glucocorticoids such as dexamethasone, prednisolones are clinically used due to their resistance to host enzymes such as 11 β-hydroxysteroid dehydrogenase-2 (11β-HSD2) that can efficiently inactivate endogenous glucocorticoids. Both endogenous and synthetic glucocorticoids act through intracellular glucocorticoid receptor (GR) encoded by nr3c1 gene. Glucocorticoids induced during infections, cancer progression and various stress responses are involved in regulating neuroendocrine processes via hypothalamic pituitary adrenal axis (HPA) and maintain homeostasis [6]. During some systemic herpesviruses and influenza virus infection, the HPA axis modulates disease severity by balancing the immunity and immunopathological responses [7,8,9]. Some of the known immunosuppressive effects of corticosteroids include a modulation of cytokine production by immune cells, an altered cellular trafficking, enhanced phagocytosis as well as the promotion of regulatory T cell function [2, 10]
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