Glucocorticoid-induced TNFR family-related protein (GITR) activation exacerbates murine asthma and collagen-induced arthritis.
Glucocorticoid-induced TNFR family-related protein (GITR) is expressed at low levels on resting T cells, B cells and macrophages but at high levels on regulatory T cells (Treg). Although GITR expression is up-regulated on CD4+ effector cells upon activation, the role of GITR in Th1 and Th2 cell development is unclear. We report here that activation of GITR signalling by anti-GITR antibody markedly enhanced the induction of both Th1 and Th2 cytokine production by naive CD4+CD25- T cells. Consistent with this observation, anti-GITR antibody significantly enhanced the expression of the key Th1 (T-bet) and Th2 (GATA3) transcription factors in vitro. Administration of anti-GITR mAb in a murine model of arthritis significantly exacerbated the severity and onset of joint inflammation with elevated production of TNF-alpha, IFN-gamma, IL-5, and collagen-specific IgG1. Administration of anti-GITR mAb also significantly exacerbated murine allergic airways inflammation with elevated production of OVA-specific IFN-gamma, IL-2, IL-4, IL-5, and IgE. Finally, we demonstrated that adoptive transfer of CD4+GITR+ T cells effectively abolished airway inflammation induced in SCID mice reconstituted with CD4+GITR- T cells. Our results therefore provide direct evidence that GITR can modulate both Th1- and Th2-mediated inflammatory diseases, and may be a potential target for therapeutic intervention.
Patel
Manish
M
Division of Immunology, Infection and Inflammation, University of Glasgow, Glasgow, UK.
Xu
Damo
D
Kewin
Pete
P
Choo-Kang
Brian
B
McSharry
Charles
C
Thomson
Neil C
NC
Liew
Foo Y
FY
D000276:Adjuvants, Immunologic / Q000502:physiology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000502:physiology; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism*; D001249:Asthma / Q000378:metabolism*; D002478:Cells, Cultured; D003094:Collagen / Q000276:immunology*; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein; D005938:Glucocorticoids / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D016513:Mice, SCID; D017475:Receptors, Nerve Growth Factor / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
D000276:Adjuvants, Immunologic; D000911:Antibodies, Monoclonal; D053450:Glucocorticoid-Induced TNFR-Related Protein; D005938:Glucocorticoids; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; D003094:Collagen