Distinct classes of protective immunity are guided by activation of STAT transcription factor (TF) family members in response to environmental cues. CD4+ regulatory T cells (Tregs) suppress excessive immune responses, and their deficiency results in a lethal, multi-organ autoimmune syndrome characterized by T helper 1 (Th1) and T helper 2 (Th2) CD4+ T cell-dominated lesions. Here we show that pathogenic Th17 responses in mice are also restrained by Tregs. This suppression was lost upon Treg-specific ablation of Stat3, a TF critical for Th17 differentiation, and resulted in the development of a fatal intestinal inflammation. These findings suggest that Tregs adapt to their environment by engaging distinct effector response-specific suppression modalities upon activation of STAT proteins that direct the corresponding class of the immune response.

The transcription factor Foxp3 is indispensible for the differentiation and function of regulatory T cells (Treg cells). To gain insights into the molecular mechanisms of Foxp-mediated gene expression we purified Foxp3 complexes and explored their composition. Biochemical and mass-spectrometric analyses revealed that Foxp3 forms multi-protein complexes of 400–800 kDa or larger and identified 361 associated proteins, ~30% of which are transcription-related. Foxp3 directly regulated expression of a large proportion of the genes encoding its co-factors. Reciprocally, some transcription factor partners of Foxp3 facilitated its expression. Functional analysis of Foxp3 cooperation with one such partner, GATA-3, provided further evidence for a network of transcriptional regulation afforded by Foxp3 and its associates to control distinct aspects of Treg cell biology.

The 138 genes encoding the 79 ribosomal proteins (RPs) of Saccharomyces cerevisiae form the tightest cluster of coordinately regulated genes in nearly all transcriptome experiments. The basis for this observation remains unknown. We now provide evidence that two factors, Fhl1p and Ifh1p, are key players in the transcription of RP genes. Both are found at transcribing RP genes in vivo. Ifh1p, but not Fhl1p, leaves the RP genes when transcription is repressed. The occupancy of the RP genes by Ifh1p depends on its interaction with the phospho-peptide recognizing forkhead-associated domain of Fhl1p. Disruption of this interaction is severely deleterious to ribosome synthesis and cell growth. Loss of functional Fhl1p leads to cells that have only 20% the normal amount of RNA and that synthesize ribosomes at only 5-10% the normal rate. Homeostatic mechanisms within the cell respond by reducing the transcription of rRNA to match the output of RPs, and by reducing the global transcription of mRNA to match the capacity of the translational apparatus.

Transient ablation of regulatory T cells in a murine model of breast carcinogenesis inhibits primary tumor and lung metastatic growth and enhances the therapeutic effect of radiotherapy, but not immune checkpoint blockade.

Foxp3 plays an indispensable role in establishing stable transcriptional and functional programs of regulatory T (Treg) cells. Loss of Foxp3 expression in mature Treg cells results in a failure of suppressor function, yet the molecular mechanisms ensuring steady heritable Foxp3 expression in the Treg cell lineage remain unknown. Using Treg cell-specific gene targeting we found that Runx-CBFβ complexes were required for maintenance of Foxp3 mRNA and protein expression in Treg cells. Consequently, mice lacking CBFβb exclusively in the Treg cell lineage exhibited a moderate lymphproliferative syndrome. Thus, Runx-CBFβ complexes maintain stable expression of high amounts of Foxp3 and serve as an essential determinant of Treg cell lineage stability.

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CD4+Foxp3+ regulatory T-cells (Tregs) are a unique subset of helper T-cells, which regulate immune response and establish peripheral tolerance. Tregs not only maintain the tone and tenor of an immune response by dominant tolerance but, in recent years, have also been identified as key players in resolving tissue inflammation and as mediators of tissue healing. Apart from being diverse in their origin (thymic and peripheral) and location (lymphoid and tissue resident), Tregs are also phenotypically heterogeneous as per the orientation of ongoing immune response. In this review, we discuss the recent advances in the field of Treg biology in general, and non-lymphoid and tissue-resident Tregs in particular. We elaborate upon well-known visceral adipose tissue, colon, skin, and tumor-infiltrating Tregs and newly identified tissue Treg populations as in lungs, skeletal muscle, placenta, and other tissues. Our attempt is to differentiate Tregs based on distinctive properties of their location, origin, ligand specificity, chemotaxis, and specific suppressive mechanisms. Despite ever expanding roles in maintaining systemic homeostasis, Tregs are employed by large varieties of tumors to dampen antitumor immunity. Thus, a comprehensive understanding of Treg biology in the context of inflammation can be instrumental in effectively managing tissue transplantation, autoimmunity, and antitumor immune responses.

The ribosomal protein genes of Saccharomyces cerevisiae, responsible for nearly 40% of the polymerase II transcription initiation events, are characterized by the constitutive tight binding of the transcription factor Rap1. Rap1 binds at many places in the yeast genome, including glycolytic enzyme genes, the silent MAT loci, and telomeres, its specificity arising from specific cofactors recruited at the appropriate genes. At the ribosomal protein genes two such cofactors have recently been identified as Fhl1 and Ifh1. We have now characterized the interaction of these factors at a bidirectional ribosomal protein promoter by replacing the Rap1 sites with LexA operator sites. LexA-Gal4(AD) drives active transcription at this modified promoter, although not always at the correct initiation site. Tethering Rap1 to the promoter neither drives transcription nor recruits Fhl1 or Ifh1, showing that Rap1 function requires direct DNA binding. Tethering Fhl1 also fails to activate transcription, even though it does recruit Ifh1, suggesting that Fhl1 does more than simply provide a platform for Ifh1. Tethering Ifh1 to the promoter leads to low-level transcription, at the correct initiation sites. Remarkably, activation by tethered LexA-Gal4(AD) is strongly reduced when TOR kinase is inhibited by rapamycin. Thus, TOR can act independently of Fhl1/Ifh1 at ribosomal protein promoters. We also show that, in our strain background, the response of ribosomal protein promoters to TOR inhibition is independent of the Ifh1-related protein Crf1, indicating that the role of this corepressor is strain specific. Fine-structure chromatin mapping of several ribosomal protein promoters revealed that histones are essentially absent from the Rap1 sites, while Fhl1 and Ifh1 are coincident with each other but distinct from Rap1.The 138 genes encoding the 79 ribosomal proteins (RP) of Saccharomyces cerevisiae are arguably the most coordinately regulated cluster of genes, spread throughout the yeast genome (7, 11). It was originally thought that the basis for much of this regulation lay in the presence of binding sites for the protein Rap1 upstream of a large majority of the RP genes (17, 21).However, Rap1 is a protein of many functions (reviewed by references 28 and 29). It is the primary transcription factor for the glycolytic genes and several translation factor genes. It acts as the major duplex DNA binding protein of telomeres. It nucleates the silencing of the HML and HMR mating-type loci. Genome-wide chromatin immunoprecipitation (ChIP) analysis revealed that Rap1 binds to about 5% of yeast genes and participates in the activation of 37% of RNA polymerase II transcripts in exponentially growing yeast cells (21). There is good evidence that the initial step of Rap1 is to clear nucleosomes from a patch of DNA (28,40) and that the second step is to recruit specific factors to carry out the appropriate function. It is now clear that for the RP genes these factors are Fhl1 and Ifh1, which are found almost exclusively at RP genes. Gcr1 and Gcr2 ...