Glucocorticoid‐induced tumour necrosis factor receptor family‐related receptor signalling exacerbates hapten‐induced colitis by CD4+ T cells

Summary The glucocorticoid‐induced tumour necrosis factor receptor family related gene (GITR) has been reported to be expressed on the activated T and CD4+CD25+ regulatory T cells (Treg). Signalling triggered by GITR not only neutralizes the suppressive effect of Treg cells, but also augments activation, proliferation and cytokine production of effector T cells. To test the role of GITR in 2,4,6‐trinitrobenzene sulphonic acid (TNBS)‐induced colitis − a murine model of mucosal inflammation − TNBS‐injected Balb/c mice were treated with agonistic anti‐GITR monoclonal antibody (mAb). Anti‐GITR treatment increased the death rate compared to rat IgG‐treated mice. Typically, death occurred within 4 days after the TNBS injection when the mice were treated with anti‐GITR. The mice that survived anti‐GITR treatment suffered from severe inflammation in their entire intestines. CD4+ T‐depletion protected the mice from colitis; even an anti‐GITR effect was not apparent. In contrast, CD8+ T depletion showed less protective than did CD4+ T depletion. Stimulation of GITR enhanced the production of proinflammatory cytokines including interferon (IFN)‐γ, tumour necrosis factor (TNF)‐α, interleukin (IL)‐6 and IL‐12. It also enhanced the humoral response such as serum levels of IgG2b and IgA, which was completely dependent on CD4+ T cells. Taken together, this study demonstrated that GITR signalling on CD4+ T cells is involved in the development and progress of colitis by enhancing both T helper type 1 (Th1) and Th2 type responses.