GATA3-driven Th2 responses inhibit TGF-beta1-induced FOXP3 expression and the formation of regulatory T cells.

Transcription factors act in concert to induce lineage commitment towards Th1, Th2, or T regulatory (Treg) cells, and their counter-regulatory mechanisms were shown to be critical for polarization between Th1 and Th2 phenotypes. FOXP3 is an essential transcription factor for natural, thymus-derived (nTreg) and inducible Treg (iTreg) commitment; however, the mechanisms regulating its expression are as yet unknown. We describe a mechanism controlling iTreg polarization, which is overruled by the Th2 differentiation pathway. We demonstrated that interleukin 4 (IL-4) present at the time of T cell priming inhibits FOXP3. This inhibitory mechanism was also confirmed in Th2 cells and in T cells of transgenic mice overexpressing GATA-3 in T cells, which are shown to be deficient in transforming growth factor (TGF)-beta-mediated FOXP3 induction. This inhibition is mediated by direct binding of GATA3 to the FOXP3 promoter, which represses its transactivation process. Therefore, this study provides a new understanding of tolerance development, controlled by a type 2 immune response. IL-4 treatment in mice reduces iTreg cell frequency, highlighting that therapeutic approaches that target IL-4 or GATA3 might provide new preventive strategies facilitating tolerance induction particularly in Th2-mediated diseases, such as allergy

Transforming growth factor-beta: Recent advances on its role in immune tolerance.

Transforming growth factor (TGF-β1) is a pleiotropic cytokine, secreted by immune and nonhematopoietic cells. TGF-β is involved in many different critical processes, such as embryonal development, cellular maturation and differentiation, wound healing, and immune regulation. It maintains immune homeostasis by acting as a potent immune suppressor through inhibition of proliferation, differentiation, activation, and effector function of immune cells. Paradoxically, depending on the context, it displays proinflammatory properties by being a potent chemoattractant for neutrophils and promoting inflammation. In addition, it does not only induce differentiation into the anti-inflammatory Treg cells, but also into the proinflammatory Th17 and Th9 cells and inhibits Th22 differentiation. TGF-β has been demonstrated to be involved in multiple pathologies. In infections, it protects against collateral damages caused by the immune system, but it also promotes immune evasion and chronic infections. In autoimmune diseases, a TGF-β dysfunction leads to the loss of tolerance to self-antigens. In cancer, TGF-β is a potent inhibitor of cell proliferation and acts as a tumor suppressor at the beginning of tumorogenesis. However, once the cells become resistant to TGF-β, it mainly supports tumor growth and metastasis by promoting immune evasion and angiogenesis. In asthma, it is assumed to promote allergen tolerance, but plays a detrimental role in irreversible remodeling of the airways. Despite the high numbers of TGF-β-targeted pathways, it is a promising drug target for treatment of autoimmunity, cancer, fibrosis, if cell specificity can be achieved.This review summarizes the progresses that have been accomplished on the understanding of TGF-β's signaling in the immune homeostasis and its role in pathogenesis

RORC2 is involved in T cell polarization through interaction with the FOXP3 promoter.

The process of Th cell differentiation toward polarized effector T cells tailors specific immunity against invading pathogens while allowing tolerance against commensal microorganisms, harmless allergens, or autologous Ags. Identification of the mechanisms underlying this polarization process is therefore central to understand how the immune system confers immunity and tolerance. The present study demonstrates that retinoic acid receptor-related orphan receptor C2 (RORC2), a key transcription factor in Th17 cell development, inhibits FOXP3 expression in human T cells. Although overexpression of RORC2 in naive T cells reduces levels of FOXP3, small interfering RNA-mediated knockdown of RORC2 enhances its expression. RORC2 mediates this inhibition at least partially by binding to two out of four ROR-responsive elements on the FOXP3 promoter. Knockdown of RORC2 promotes high FOXP3 levels and decreased expression of proinflammatory cytokines beta form of pro-IL-1, IL-6, IL-17A, IFN-gamma, and TNF-alpha in differentiating naive T cells, suggesting that the role of RORC2 in Th17 cell development involves not only induction of Th17-characteristic genes, but also suppression of regulatory T cell-specific programs. Together, this study identifies RORC2 as a polarizing factor in transcriptional cross-regulation and provides novel viewpoints on the control of immune tolerance versus effector immune responses

Population genetics of the Chilean frog Batrachyla Leptopus (Leptodactylidae)

Electrophoretic variation of proteins encoded by 14 loci was analyzed in eight (five continental and three insular) populations of the Chilean leptodactylid frog Batrachyla leptopus. The overall proportion of polymorphic loci was estimated to be 18.7% and the average number of alleles per locus, 1.2, while observed and expected heterozygosities were 1.7 and 5.1%, respectively. The estimated coefficient of genetic identity was 0.940; the corresponding figure for genetic distance was 0.063. F-statistics analysis showed a total inbreeding coefficient (Fit) of 0.855 and high levels of genetic subdivision (Fst = 0.596) as well as of inbreeding within populations (Fis = 0.640). However, there was only a moderate level of genetic differentiation (Fst = 0.181) between the insular group of populations and the continental group.<br>A variação eletroforética de proteínas codificadas por 14 loci foi analisada em oito populações (5 continentais e 3 insulares) da rã leptodactilídea chilena Batrachyla leptopus. A proporção geral de loci polimórficos foi estimada como sendo de 18,7% e o número médio de alelos por loco, 1,2, enquanto que as heterozigosidades observada e esperada foram 1,7 e 5,1%, respectivamente. O coeficiente esperado de identidade genética foi 0,940; o número correspondente para a distância genética foi 0,063. A análise estatística F mostrou um coeficiente de endogamia total (Fit) de 0,855 e altos níveis de subdivisão genética (Fst = 0,596), assim como de endogamia dentro das populações (Fis = 0,640). Contudo, houve apenas um nível moderado de diferenciação genética (Fst = 0,181) entre o grupo insular de populações e o grupo continental