Glucocorticoid-induced tumour necrosis factor receptor family-related receptor signalling exacerbates hapten-induced colitis by CD4+ T cells.
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)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-12. It also enhanced the humoral response such as serum levels of IgG(2b) 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.
Lee
Sun K
SK
The Immunomodulation Research Center, University of Ulsan, Ulsan, Korea.
Choi
Beom K
BK
Kim
Young H
YH
Kang
Woo J
WJ
Kim
Kwang H
KH
Sakaguchi
Shimon
S
Suh
Jae H
JH
Kim
Tae Y
TY
Kwon
Byoung S
BS
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006241:Haptens; D018928:Immunity, Mucosal; D007070:Immunoglobulin A / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000096:biosynthesis; D015212:Inflammatory Bowel Diseases / Q000139:chemically induced / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology; D014302:Trinitrobenzenesulfonic Acid
D016207:Cytokines; D053450:Glucocorticoid-Induced TNFR-Related Protein; D006241:Haptens; D007070:Immunoglobulin A; D007074:Immunoglobulin G; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; D014302:Trinitrobenzenesulfonic Acid