한빛사 논문
Sung Woong Janga,1, Soo Seok Hwanga,b,1, Hyeong Su Kima, Min Kyung Kima, Woo Ho Leea, Soh Un Hwanga, Jinu Gwakb, Si Kyoung Yewb, Richard A. Flavellb,c,2,3, and Gap Ryol Leea,2,3
a Department of Life Science, Sogang University, 04107 Seoul, Korea; b Department of Immunobiology, Yale University, New Haven, CT 06520; and c Howard Hughes Medical Institute, Yale University, New Haven, CT 06520
1 S.W.J. and S.S.H. contributed equally to this work.
2 R.A.F. and G.R.L. contributed equally to this work.
3 To whom correspondence may be addressed.
Abstract
Regulatory T (Treg) cells play an essential role in maintaining immune homeostasis, but the suppressive function of Treg cells can be an obstacle in the treatment of cancer and chronic infectious diseases. Here, we identified the homeobox protein Hhex as a negative regulator of Treg cells. The expression of Hhex was lower in Treg cells than in conventional T (Tconv) cells. Hhex expression was repressed in Treg cells by TGF-β/Smad3 signaling. Retroviral overexpression of Hhex inhibited the differentiation of induced Treg (iTreg) cells and the stability of thymic Treg (tTreg) cells by significantly reducing Foxp3 expression. Moreover, Hhex-overexpressing Treg cells lost their immunosuppressive activity and failed to prevent colitis in a mouse model of inflammatory bowel disease (IBD). Hhex expression was increased; however, Foxp3 expression was decreased in Treg cells in a delayed-type hypersensitivity (DTH) reaction, a type I immune reaction. Hhex directly bound to the promoters of Foxp3 and other Treg signature genes, including Il2ra and Ctla4, and repressed their transactivation. The homeodomain and N-terminal repression domain of Hhex were critical for inhibiting Foxp3 and other Treg signature genes. Thus, Hhex plays an essential role in inhibiting Treg cell differentiation and function via inhibition of Foxp3.
regulatory T cell, Hhex, Foxp3
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