In vivo kinetics of GITR and GITR ligand expression and their functional significance in regulating viral immunopathology.
This report evaluates the role of interaction between glucocorticoid-induced tumor necrosis factor receptor (GITR) and GITR ligand (GITR-L) in the immuno-inflammatory response to infection with herpes simplex virus (HSV). Both GITR and GITR-L were transiently upregulated after ocular HSV infection, on antigen-specific T cells and antigen-presenting cells, respectively, in the draining lymph node (DLN). In addition, virus-specific T-cell responses in the DLN and spleen were enhanced by anti-GITR antibody treatment, an outcome expected to result in more severe inflammatory lesions. Intriguingly, the treatment resulted in significantly diminished T-cell-mediated ocular lesions. The explanation for these findings was that anti-GITR antibody treatment caused a reduced production of ocular MMP-9, a molecule involved in ocular angiogenesis, an essential step in the pathogenesis of herpetic keratitis. Our results are the first observations to determine in vivo kinetics of GITR and GITR-L expression after virus infection, and they emphasize the role of GITR-GITR-L interaction to regulate virus-induced immuno-inflammatory lesions.
Suvas
Susmit
S
Department of Microbiology, M409, Walters Life Sciences Building, University of Tennessee, Knoxville, TN 37996-0845, USA. ssuvas@utk.edu
Kim
Bumseok
B
Sarangi
Pranita P
PP
Tone
Masahide
M
Waldmann
Herman
H
Rouse
Barry T
BT
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000938:Antigen-Presenting Cells / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein; D018259:Herpesvirus 1, Human / Q000276:immunology* / Q000502:physiology; D016849:Keratitis, Herpetic / Q000276:immunology / Q000473:pathology / Q000821:virology; D007700:Kinetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D048069:Tumor Necrosis Factors; D015854:Up-Regulation
D000911:Antibodies, Monoclonal; D002352:Carrier Proteins; D053450:Glucocorticoid-Induced TNFR-Related Protein; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; C478966:Tnfsf18 protein, mouse; D048069:Tumor Necrosis Factors; D020780:Matrix Metalloproteinase 9