T regulatory cells maintain intestinal homeostasis by suppressing gd T cells

Park SG, et al. Immunity. 33:791-803 (2010)

Speaker：Wan-Chen Chung (鍾宛臻)                Time ：13:00~14:00, Mar. 30, 2011

Commentator：Dr. Jiu-Yao Wang (王志堯醫師)       Place：Room 601

Abstract:

Inflammatory bowel disease (IBD) , including ulcerative colitis (UC) and Crohn’s disease (CD), are immune-mediated disorders of the intestine. Previous studies have shown that enteric commensal bacteria play a role in the inflammatory responses in the intestine, and immune tolerance toward normal commensal bacteria is important for maintaining intestinal immune homeostasis. TCRgd⁺ T cell are a subpopulation of T cells, they are more abundant in the intraepithelial lymphocyte (IEL) compartment than peripheral blood. In human disease such as UC and collagen-induced arthritis mouse model, it has been reported that TCRgd⁺ T cells are abundant in the inflamed region. However, in the dextran sulfate sodium (DSS)-induced experimental colitis model, TCRgd⁺ T cell were found to be important for immunoregulation. So it remains unclear whether TCRgd⁺ T cell are immune regulators or mediators in IBD. In the authors’ previous studies, it was found that deletion of the phosphoinositide-dependent protein kinase 1 (pdk1) gene by Cd4-Cre significantly affects CD4⁺ T cell activation, but gd T cells and natural killer cells were more abundant in the periphery. In this study, the pdk1^flox/flox; Cd4-Cre mice had spontaneous colitis. In of pdk1^flox/flox; Cd4-Cre mice, proinflammatory cytokines IL-17,IL-23 and TNF-a were increased in the colon. Activated TCRgd⁺ T cell were also increased in the IEL compartment. By double-deletion of pdk1and TCRd gene, they proved that TCRgd⁺ T cell play a role in inducing colitis. Treatment the pdk1^flox/flox; Cd4-Cre mice with Sulfatrim abrogated the colitis, suggesting that activated TCRgd⁺ T cell were response to the commensal bacteria, thus lead to colitis. Then they demonstrated that PDK1 is required for Treg activation and function, explaining that PDK1-deficient Treg failure to regulate TCRgd⁺ T cell in pdk1^flox/flox;Cd4-Cre mice. Finally, they showed that adoptive transfer WT Treg can suppress TCRgd⁺ T cell by secreting inhibitory cytokine IL-10. Here the authors show thatTreg cells were important in regulating TCRgd⁺ T cell responses to commensal bacteria. This regulatory mechanism is important for maintaining enteric immune homeostasis.

References:

1. Nanno, M. et al. gd T cells: Firefighters or fire boosters in the front lines of inflammatory responses. Immunol. Rev. 215,103-113. (2007)
2. Park SG, et al. The kinase PDK1 integrates T cell antigen receptor and CD28 coreceptor signaling to induce NF-kappaB and activate T cells. Nat. Immunol. 10: 158-166. (2009)