Abstract
Ocular herpes simplex virus infection can cause a blinding CD4+ T cell orchestrated immuno-inflammatory lesion in the cornea called Stromal Keratitis (SK). A key to controlling the severity of SK lesions is to suppress the activity of T cells that orchestrate lesions and enhance the representation of regulatory cells that inhibit effector cell function. In this report we show that a single administration of TCDD (2, 3, 7, 8- Tetrachlorodibenzo-p-dioxin), a non-physiological ligand for the AhR receptor, was an effective means of reducing the severity of SK lesions. It acted by causing apoptosis of Foxp3- CD4+ T cells but had no effect on Foxp3+ CD4+ Tregs. TCDD also decreased the proliferation of Foxp3- CD4+ T cells. The consequence was an increase in the ratio of Tregs to T effectors which likely accounted for the reduced inflammatory responses. In addition, in vitro studies revealed that TCDD addition to anti-CD3/CD28 stimulated naïve CD4+ T cells caused a significant induction of Tregs, but inhibited the differentiation of Th1 and Th17 cells. Since a single TCDD administration given after the disease process had been initiated generated long lasting anti-inflammatory effects, the approach holds promise as a therapeutic means of controlling virus induced inflammatory lesions.
Highlights
Ocular infection with herpes simplex virus (HSV) can result in a chronic immuno-inflammatory reaction in the cornea which represents a common cause of human blindness [1,2]
We showed that a single administration of TCDD, a stable agonist of the aryl hydrocarbon receptor, significantly reduced the severity of herpes keratitis lesions
The outcome of the therapy was a change in the balance of effector cells responsible for orchestrating lesions, with regulatory cells able to inhibit the inflammatory effects of the effectors
Summary
Ocular infection with herpes simplex virus (HSV) can result in a chronic immuno-inflammatory reaction in the cornea which represents a common cause of human blindness [1,2]. The severity of SK can be influenced by the balance of CD4+ effector T cells and Foxp3+ regulatory T cells (Treg) [5,6]. Procedures that change this balance represent a promising approach for therapy. This has been achieved either by adoptive transfer with Treg populations [6] or the repeated administration of reagents that can cause naıve CD4+ T cells to convert to become Treg [7,8]. Procedures that could shift the balance of T effectors and Treg after a single drug administration would represent a convenient maneuver
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