Foxp3 drives oxidative phosphorylation and protection from lipotoxicity.

Tregs can adopt a catabolic metabolic program with increased capacity for fatty acid oxidation-fueled oxidative phosphorylation (OXPHOS). It is unclear why this form of metabolism is favored in Tregs and, more specifically, whether this program represents an adaptation to the environment and developmental cues or is "hardwired" by Foxp3. Here we show, using metabolic analysis and an unbiased mass spectroscopy-based proteomics approach, that Foxp3 is both necessary and sufficient to program Treg-increased respiratory capacity and Tregs' increased ability to utilize fatty acids to fuel oxidative phosphorylation.

The Regulatory T Cell Lineage Factor Foxp3 Regulates Gene Expression through Several Distinct Mechanisms Mostly Independent of Direct DNA Binding.

The lineage factor Foxp3 is essential for the development and maintenance of regulatory T cells, but little is known about the mechanisms involved. Here, we demonstrate that an N-terminal proline-rich interaction region is crucial for Foxp3's function. Subdomains within this key region link Foxp3 to several independent mechanisms of transcriptional regulation.

An atlas of mouse CD4(+) T cell transcriptomes.

Background: CD4(+) T cells are key regulators of the adaptive immune system and can be divided into T helper (Th) cells and regulatory T (Treg) cells. During an immune response Th cells mature from a naive state into one of several effector subtypes that exhibit distinct functions. The transcriptional mechanisms that underlie the specific functional identity of CD4(+) T cells are not fully understood.

Peak inflammation in atherosclerosis, primary biliary cirrhosis and autoimmune arthritis is counter-intuitively associated with regulatory T cell enrichment.

Regulatory T cells (Treg) influence the development of autoimmunity and their use is increasingly proposed for clinical applications. The well-characterized suppressive potential of Treg frequently leads to the assumption that Treg presence in prevailing numbers is indicative of immunosuppression. We hypothesized that this assumption may be false.

Foxp3 expression is required for the induction of therapeutic tissue tolerance.

CD4(+)Foxp3(+) regulatory T cells (Treg) are essential for immune homeostasis and maintenance of self-tolerance. They are produced in the thymus and also generated de novo in the periphery in a TGF-β-dependent manner. Foxp3(+) Treg are also required to achieve tolerance to transplanted tissues when induced by coreceptor or costimulation blockade.

Activation rather than Foxp3 expression determines that TGF-β-induced regulatory T cells out-compete naïve T cells in dendritic cell clustering.

Regulatory T (Treg) cells are critically important for the maintenance of immunological tolerance. Both centrally arising natural nTreg cells and those emerging in the periphery in response to TGF-β, iTreg cells, play a role in the control of unwanted immune responses. Treg cells adopt multiple mechanisms to inhibit effector T cells, yet it is unclear whether these mechanisms are shared by nTreg cells and iTreg cells alike.

Comparative Genomics Reveals Key Gain-of-Function Events in Foxp3 during Regulatory T Cell Evolution.

The immune system has the ability to suppress undesirable responses, such as those against commensal bacteria, food, and paternal antigens in placenta pregnancy. The lineage-specific transcription factor Foxp3 orchestrates the development and function of regulatory T cells underlying this immunological tolerance. Despite the crucial role of Foxp3 in supporting immune homeostasis, little is known about its origin, evolution, and species conservation.

Regulatory T cells protect from autoimmune arthritis during pregnancy.

Pregnancy frequently has a beneficial effect on the autoimmune disease Rheumatoid Arthritis, ranging from improvement in clinical symptoms to complete remission. Despite decades of study, a mechanistic explanation remains elusive. Here, we demonstrate that an analogous pregnancy-induced remission can be observed in a mouse model of arthritis.

The role of galectin-1 in trophoblast differentiation and signal transduction.

Galectins are proteins with the ability to bind β-galactosides through a conserved carbohydrate recognition domain. Galectin-1 exerts its biological effects by binding glycan ligands on proteins involved in cell adhesion and growth regulation. Galectin-1 inhibits trophoblast cell proliferation and induces syncytium formation.

Foxp3 interacts with c-Rel to mediate NF-κB repression.

Expression of the lineage-specific DNA-binding factor Foxp3 controls the development and function of naturally occurring regulatory T cells. Foxp3 has been shown to interact with a multitude of transcriptional regulators including NFAT, NF-κB (p65), Runx1 and RORγt, as well as the histone modification enzymes TIP60, HDAC7 and HDAC9. The sum of these interactions is believed to cause the change in the transcriptional program of regulatory T cells.

Gimme shelter: the immune system during pregnancy.

Antigen-presenting molecules vary between individuals of the same species, making it more difficult for pathogens to evade immune recognition and spread through the whole population. As a result of this genetic diversity, transplants between individuals are recognized as foreign and are rejected. This alloreactivity turns placental viviparity into a major immunological challenge.

Live imaging of dendritic cell-Treg cell interactions.

The decision to launch an immune response is made during the interaction of helper T cells and regulatory T cells with dendritic cells. Recognition of antigen leads to formation of immunological synapses at the interface between the cells and to activation of the T cells. The length of interaction between the T cells and dendritic cells influences the functional outcome.

Shine a light: imaging the immune system.

Intra vital microscopy and whole-body imaging promise to revolutionize how we study the immune system. They compel by the intrinsic beauty of the images obtained and the undeniable direct biological relevance of the observations. However, it is important to remember that in many cases, fundamental insights into the underlying biological processes have already been obtained using ex vivo reductionist approaches.

Specific immunosuppression with inducible Foxp3-transduced polyclonal T cells.

Forkhead box p3 (Foxp3)-expressing regulatory T cells are key mediators of peripheral tolerance suppressing undesirable immune responses. Ectopic expression of Foxp3 confers regulatory T cell phenotype to conventional T cells, lending itself to therapeutic use in the prevention of autoimmunity and transplant rejection. Here, we show that adoptive transfer of polyclonal, wild-type T cells transduced with an inducible form of Foxp3 (iFoxp3) can be used to suppress immune responses on demand.

Neuropilin-1 expression on regulatory T cells enhances their interactions with dendritic cells during antigen recognition.

The interaction of T cells with dendritic cells (DCs) determines whether an immune response is launched or not. Recognition of antigen leads to formation of immunological synapses at the interface between the cells. The length of interaction is likely to determine the functional outcome, because it limits the number of MHC class II-peptide complexes that can be recruited into the synapse.

Tolerance signaling molecules and pregnancy: IDO, galectins, and the renaissance of regulatory T cells.

Problem: Is the concept of maternal tolerance preventing rejection of the semi-allogeneic 'fetal allograft' still valid?

Method Of Study: Compilation of expert reviews of literature and recent advances in research on indoleamine-2,3 dioxygenase (IDO), regulatory T cells and galectin-1.

Results And Conclusion: A role for IDO in pregnancy success remains speculative, but solid data exist to support a role for Treg cells, and for galectin-1 in induction and action of Treg cells. Just as several signals may need to be simultaneously present to induce Th1 cytokine-triggered abortions, more than 1 signal may need to be simultaneously present to prevent rejection and ensure success.

Periodic accumulation of regulatory T cells in the uterus: preparation for the implantation of a semi-allogeneic fetus?

Background: Naturally occurring Foxp3(+)regulatory T cells play an important role in the inhibition of an immunological attack of the fetus. As implantation of the fetus poses an immediate antigenic challenge, the immune system has to prepare itself for this event prior to implantation.

Methodology And Principal Findings: Here, we show using quantitative RT-PCR and flow cytometry that regulatory T cells accumulate in the uterus not only during pregnancy, but also every time the female becomes fertile.

Alloantigen-enhanced accumulation of CCR5+ 'effector' regulatory T cells in the gravid uterus.

Regulatory T cells play an essential role in preventing fetal rejection by the maternal immune system. Here we show that, based on the expression of CCR5, regulatory T cells can be divided into a highly suppressive CCR5+ and a far less suppressive CCR5- subpopulation, suggesting that the former represent the effector arm of regulatory T cells. Although regulatory T cells from CCR5-/- gene deletion mutants still suppress, they are less effective mediators of maternal-fetal tolerance.

The role of regulatory T cells in alloantigen tolerance.

The diversification mechanism used by the adaptive immune system to maximize the recognition of foreign antigens has the side effect of generating autoreactivity. This effect is counteracted by deletion of cells expressing receptors with high affinity to self (central tolerance) and suppression of autoreactive cells by regulatory T cells (Tregs; peripheral tolerance). This understanding led to the notion that Tregs represent a specialized subset of autoreactive T cells with inhibitory function.

Mother's little helpers: mechanisms of maternal-fetal tolerance.

The evolutionary adaptation in mammals that allows implantation of their embryos in the mother's womb creates an immunological problem. Although it ensures optimal nourishment and protection of the fetus throughout its early development, intimate contact with the mother's uterine tissue makes the fetus a potential target for her immune system. As half the fetal genes are derived from the father, the developing embryo and placenta must be considered a 'semi-allograft'.

Tolerance, suppression and the fetal allograft.

In solid organ transplantation the recipient immune system recognises foreign alloantigens expressed by the graft. This results in an immune attack of the transplanted organ leading to rejection, which can be prevented only by therapeutic immunosuppression. During pregnancy the fetus should also be rejected by the maternal immune system, since it expresses antigens derived from the father.

Regulatory T cells mediate maternal tolerance to the fetus.

Pregnancy constitutes a major challenge to the maternal immune system, as it has to tolerate the persistence of paternal alloantigen. Although localized mechanisms contribute to fetal evasion from immune attack, maternal alloreactive lymphocytes persist. We demonstrate here an alloantigen-independent, systemic expansion of the maternal CD25+ T cell pool during pregnancy and show that this population contains dominant regulatory T cell activity.