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Hypersensitive site 6 of the Th2 locus control region is essential for Th2 cytokine expression
Williams, Adam,Lee, Gap Ryol,Spilianakis, Charalampos G.,Hwang, Soo Seok,Eisenbarth, Stephanie C.,Flavell, Richard A. National Academy of Sciences 2013 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.110 No.17
<P>The T helper type 2 (Th2) cytokine genes <I>Il4</I>, <I>Il5</I>, and <I>Il13</I> are contained within a 140-kb region of mouse chromosome 11 and their expression is controlled by a locus control region (LCR) embedded within this locus. The LCR is composed of a number of DNase I–hypersensitive sites (HSs), which are believed to encompass the regulatory core of the LCR. To determine the function of these sites, mutant mice were generated in which combinations of these HSs had been deleted from the endogenous LCR, and the effect on Th2 cytokine expression was assessed through the use of in vivo and in vitro models. These experiments revealed that, although all of the hypersensitive sites analyzed are important for appropriate LCR function, some sites are more important than others in regulating cytokine expression. Interestingly, each LCR mutation showed contrasting effects on cytokine expression, in some cases with mutants displaying opposing phenotypes between in vitro cultures and in vivo immunizations. These studies indicated that Rad50 hypersensitive site 6 was the singularly most important HS for Th2 cytokine expression, displaying consistent reductions in cytokine levels in all models tested. Furthermore analysis of chromatin modifications revealed that deletion of Rad50 hypersensitive site 6 impacted epigenetic modifications at the promoters of the <I>Il4</I>, <I>Il5</I>, and <I>Il13</I> genes as well as other regulatory sites within the Th2 locus.</P>
Homeobox protein Hhex negatively regulates Treg cells by inhibiting Foxp3 expression and function
Jang, Sung Woong,Hwang, Soo Seok,Kim, Hyeong Su,Kim, Min Kyung,Lee, Woo Ho,Hwang, Soh Un,Gwak, Jinu,Yew, Si Kyoung,Flavell, Richard A.,Lee, Gap Ryol National Academy of Sciences 2019 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF Vol.116 No.51
<P><B>Significance</B></P><P>Regulatory T (Treg) cells play an essential role in maintaining immune homeostasis. Studying factors that control Treg differentiation and function are critically important to understand immune homeostasis. In this manuscript, we discovered that transcription factor Hhex exerts an inhibitory effect on Treg cell differentiation and function. Hhex-overexpressing Treg cells lose their Foxp3 expression and fail to suppress immune responses. Hhex directly binds to Foxp3 protein and the <I>Foxp3</I> locus and inhibits expression of Foxp3 and its target genes. Thus, Hhex plays an essential role in inhibiting Treg cell differentiation and function via inhibition of Foxp3. This study will benefit clinical research in developing a therapeutic strategy for Treg cell-related diseases.</P><P>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). <I>Hhex</I> expression was increased; however, <I>Foxp3</I> 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 <I>Foxp3</I> and other Treg signature genes, including <I>Il2ra</I> and <I>Ctla4</I>, 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.</P>