Glucocorticoid‐induced TNFR family‐related protein (GITR) activation exacerbates murine asthma and collagen‐induced arthritis

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Abstract
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 factorsin 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‐α, IFN‐γ, 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‐γ, 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.