title: Controlling viral immuno-inflammatory lesions by modulating aryl hydrocarbon receptor signaling.
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.
authors.affiliation: Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee, United States of America.
authors.forename: Tamara
authors.initials: T
authors.lastname: Veiga-Parga
authors.forename: Amol
authors.initials: A
authors.lastname: Suryawanshi
authors.forename: Barry T
authors.initials: BT
authors.lastname: Rouse
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002469:Cell Separation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D018259:Herpesvirus 1, Human / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D016849:Keratitis, Herpetic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007166:Immunosuppressive Agents; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon