CD4(+) T cells polarize into effector Th subsets characterized by signature transcription factors and cytokines. Although T-bet drives Th1 responses and represses the alternative Th2, Th17, and ...Foxp3(+) regulatory T cell fates, the role of the T-bet-related transcription factor eomesodermin (Eomes) in CD4(+) T cells is less well understood. In this study, we analyze the expression and effects of Eomes in mouse CD4(+) T lymphocytes. We find that Eomes is readily expressed in activated CD4(+) Th1 T cells in vivo. Eomes(+) CD4(+) T cells accumulated in old mice, under lymphopenic conditions in a T cell transfer model of colitis, and upon oral Ag administration. However, despite its expression, genetic deletion of Eomes in CD4(+) T cells did not impact on IFN-γ production nor increase Th2 or Th17 responses. In contrast, Eomes deficiency favored the accumulation of Foxp3(+) cells in old mice, after in vivo differentiation of Eomes-deficient naive CD4(+) T cells, and in response to oral Ag in a cell-intrinsic way. Enforced Eomes expression during in vitro regulatory T cell induction also reduced Foxp3 transcription. Likewise, bystander Eomes-deficient CD4(+) T cells were more efficient at protecting from experimental autoimmune encephalitis compared with wild-type CD4(+) T cells. This enhanced capacity of Eomes-deficient CD4(+) T cells to inhibit EAE in trans was associated with an enhanced frequency of Foxp3(+) cells. Our data identify a novel role for Eomes in CD4(+) T cells and indicate that Eomes expression may act by limiting Foxp3 induction, which may contribute to the association of EOMES to susceptibility to multiple sclerosis.
Sustained Ag persistence in chronic infection results in a deregulated CD8(+) T cell response that is characterized by T cell exhaustion and cell death of Ag-specific CD8(+) T cells. Yet, the ...underlying transcriptional mechanisms regulating CD8(+) T cell exhaustion and cell death are poorly defined. Using the experimental mouse model of lymphocytic choriomeningitis virus infection, we demonstrate that the transcriptional regulator Id3 controls cell death of virus-specific CD8(+) T cells in chronic infection. By comparing acute and chronic infection, we showed that Id3 (-) virus-specific CD8(+) T cells were less abundant, whereas the absolute numbers of Id3 (+) virus-specific CD8(+) T cells were equal in chronic and acute infection. Phenotypically, Id3 (-) and Id3 (+) cells most prominently differed with regard to expression of the surface receptor 2B4; although Id3 (-) cells were 2B4(+), almost all Id3 (+) cells lacked expression of 2B4. Lineage-tracing experiments showed that cells initially expressing Id3 differentiated into Id3 (-)2B4(+) cells; in turn, these cells were terminally differentiated and highly susceptible to cell death under conditions of persisting Ag. Enforced Id3 expression specifically increased the persistence of 2B4(+) virus-specific CD8(+) T cells by decreasing susceptibility to Fas/Fas ligand-mediated cell death. Thus, our findings reveal that the transcriptional regulator Id3 promotes the survival of virus-specific CD8(+) T cells in chronic infection and suggest that targeting Id3 might be beneficial for preventing cell death of CD8(+) T cells in chronic infection or for promoting cell death of uncontrolled, hyperactive CD8(+) T cells to prevent immunopathology.
Adult neural stem/precursor cells (NSPCs) of the subventricular zone (SVZ) are an endogenous source for neuronal replacement in CNS disease. However, adult neurogenesis is compromised after brain ...injury in favor of a glial cell fate, which is mainly attributed to changes in the NSPC environment. Yet, it is unknown how this unfavorable extracellular environment translates into a transcriptional program altering NSPC differentiation. Here, we show that genetic depletion of the transcriptional regulator Id3 decreased the number of astrocytes generated from SVZ‐derived adult NSPCs in the cortical lesion area after traumatic brain injury. Cortical brain injury resulted in rapid BMP‐2 and Id3 up‐regulation in the SVZ stem cell niche. Id3−/− adult NSPCs failed to differentiate into BMP‐2‐induced astrocytes, while NSPCs deficient for the Id3‐controlled transcription factor E47 readily differentiated into astrocytes in the absence of BMP‐2. Mechanistically, E47 repressed the expression of several astrocyte‐specific genes in adult NSPCs. These results identify Id3 as the BMP‐2‐induced transcriptional regulator, promoting adult NSPC differentiation into astrocytes upon CNS injury and reveal a molecular link between environmental changes and NSPC differentiation in the CNS after injury.
Synopsis
Our study shows that cortical brain injury causes temporary environmental changes within the subventricular zone (SVZ) stem cell niche, resulting in an altered balance of the transcriptional regulators Id3 and E47 in neural stem/precursor cells (NSPCs), leading to preferential differentiation of NSPCs into astrocytes.
Traumatic brain injury results in increased BMP‐2 abundance in the SVZ.
Elevated BMP‐2 levels are translated into a rapid increase in Id3 expression in adult NSPC subpopulations, specifically in Olig2+ C cells and Thbs4+ SVZ‐born astrocytes.
Id3 then heterodimerizes with the bHLH transcription factor E47 and releases E47‐mediated repression of astrocyte‐specific gene expression.
Consequently, adult NSPCs preferentially differentiate into astrocytes and contribute to the cortical lesion astrocyte population.
Transcription factor interplay triggered by brain injury compromises adult neurogenesis through derepression of astrocyte‐specific gene expression.
The field of Plastic Surgery is prominent on social media around the world. Board certified plastic surgeons and societies of plastic surgery play a role in providing accurate, evidence-based ...information to the public, patients, and colleagues. The aim of this study was to explore the use of social media by European Plastic Surgery Societies. A retrospective analysis of the presence and activity of European Plastic Surgery Societies on Facebook, Twitter and Instagram was conducted between December 12.sup.th 2018 and December 12.sup.th 2019. The results have been compared to the American Society of Plastic Surgeons. Twenty, eleven and nine European societies yielded an active account on Facebook, Twitter and Instagram respectively. Only seven European societies had an account on all three platforms and were therefore considered polypresent. The amount of followers of those seven societies was significantly higher than of the others (p-value = 0.02). Their activity yielded significantly more posts on Facebook (p-value = 0.02). The American Society of Plastic Surgeons had more followers on all three platforms than all European societies combined. Social media are still rather unexploited by European Plastic Surgery Societies. A tendency towards increased visibility can be observed, yet a higher penetration is required to further educate and engage through social media. The quantitative data provided serve as reasonable foundation for further studies and a guide for growth of #PlasticSurgery.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Caveolin-1 (Cav-1) is a key organizer of membrane specializations and a scaffold protein that regulates signaling in multiple cell types. We found increased Cav-1 expression in human and murine T ...cells after allogeneic hematopoietic cell transplantation. Indeed, Cav-1−/− donor T cells caused less severe acute graft-versus-host disease (GVHD) and yielded higher numbers of regulatory T cells (Tregs) compared with controls. Depletion of Tregs from the graft abrogated this protective effect. Correspondingly, Treg frequencies increased when Cav-1−/− T cells were exposed to transforming growth factor-β/T-cell receptor (TCR)/CD28 activation or alloantigen stimulation in vitro compared with wild-type T cells. Mechanistically, we found that the phosphorylation of Cav-1 is dispensable for the control of T-cell fate by using a nonphosphorylatable Cav-1 (Y14F/Y14F) point-mutation variant. Moreover, the close proximity of lymphocyte-specific protein tyrosine kinase (Lck) to the TCR induced by TCR-activation was reduced in Cav-1−/− T cells. Therefore, less TCR/Lck clustering results in suboptimal activation of the downstream signaling events, which correlates with the preferential development into a Treg phenotype. Overall, we report a novel role for Cav-1 in TCR/Lck spatial distribution upon TCR triggering, which controls T-cell fate toward a regulatory phenotype. This alteration translated into a significant increase in the frequency of Tregs and reduced GVHD in vivo.
•Cav-1–deficient T cells preferentially differentiate into Tregs, which translates into lower GVHD severity in mice.•Reduced TCR:Lck clustering in Cav-1–deficient T cells is responsible for reduced TCR downstream signaling events promoting Treg differentiation.
To investigate the diagnostic performance and incidental lesion yield of 3T breast MRI if used as a problem-solving tool.
This retrospective, IRB-approved, cross-sectional, single-center study ...comprised 302 consecutive women (mean: 50±12 years; range: 20-79 years) who were undergoing 3T breast MRI between 03/2013-12/2014 for further workup of conventional and clinical breast findings. Images were read by experienced, board-certified radiologists. The reference standard was histopathology or follow-up ≥ two years. Sensitivity, specificity, PPV, and NPV were calculated. Results were stratified by conventional and clinical breast findings.
The reference standard revealed 53 true-positive, 243 true-negative, 20 false-positive, and two false-negative breast MRI findings, resulting in a sensitivity, specificity, PPV, and NPV of 96.4% (53/55), 92.4% (243/263), 72.6% (53/73), and 99.2% (243/245), respectively. In 5.3% (16/302) of all patients, incidental MRI lesions classified BI-RADS 3-5 were detected, 37.5% (6/16) of which were malignant. Breast composition and the imaging findings that had led to referral had no significant influence on the diagnostic performance of breast MR imaging (p>0.05).
3T breast MRI yields excellent diagnostic results if used as a problem-solving tool independent of referral reasons. The number of suspicious incidental lesions detected by MRI is low, but is associated with a substantial malignancy rate.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The transcription factor Foxp3 dominantly controls regulatory T (Treg) cell function, and only its continuous expression guarantees the maintenance of full Treg cell-suppressive capacity. However, ...transcriptional regulators maintaining Foxp3 transcription are incompletely described. Here, we report that high E47 transcription factor activity in Treg cells resulted in unstable Foxp3 expression. Under homeostatic conditions, Treg cells expressed high levels of the E47 antagonist Id3, thus restricting E47 activity and maintaining Foxp3 expression. In contrast, stimulation of Id3-deficient or E47-overexpressing Treg cells resulted in the loss of Foxp3 expression in a subset of Treg cells in vivo and in vitro. Mechanistic analysis indicated that E47 activated expression of the transcription factor Spi-B and the suppressor of cytokine signaling 3 (SOCS3), which both downregulated Foxp3 expression. These findings demonstrate that the balance of Id3 and E47 controls the maintenance of Foxp3 expression in Treg cells and, thus, contributes to Treg cell plasticity.
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•Id3−/− Treg cells lose expression of Foxp3 upon stimulation•The balance of Id3 and E47 controls Foxp3 transcription in established Treg cells•High E47 activity increases Spib and Socs3 transcription in Treg cells•Spi-B and SOCS3 repress Foxp3 expression
Stable Foxp3 expression is instrumental for Treg cell function. Rauch et al. found that the transcriptional regulator Id3 maintains Foxp3 transcription in established Treg cells by restricting E47 transcription factor activity. They suggest that a dynamic modulation of the Id3-E47 balance could transiently alter Treg cell function during immune responses.
Foxp3
regulatory T (Treg) cells are broadly divided into naive-like and activated Treg cells, however recent studies suggest further Treg cell heterogeneity. Treg cells contribute to impaired T cell ...responses in chronic infections, but the role of specific Treg cell subpopulations in viral infections is not well defined. Here, we report that activated Treg cells are separated into two transcriptionally distinct subpopulations characterized by low or high expression of the transcriptional regulator
.
Treg cells are a highly suppressive Treg cell subpopulation, expressing elevated levels of immunomodulatory molecules and are capable of broadly targeting T cell responses. Viral infection and interleukin-2 promote the differentiation of
into
Treg cells and during chronic infection
Treg cells are the predominant Treg cell population. Thus, our report provides a framework, in which different activated Treg cell subpopulations specifically affect immune responses, possibly contributing to T cell dysfunction in chronic infections.
Group B streptococci, a major cause of sepsis, induce inflammatory cytokines in strict dependence on bacterial ssRNA and the host molecules MyD88 and UNC-93B. In this study, we show that NO plays an ...important role in Group B streptococci-induced transcriptional activation of cytokine genes. Phagocytosis induced NO in a MyD88-dependent fashion. In turn, NO propagated the acidification of phagosomes and the processing of phagosomal bacterial nucleic acids and was required for potent transcriptional activation of cytokine genes by streptococci. This NO-dependent amplification loop has important mechanistic implications for the anti-streptococcal macrophage response and sepsis pathogenesis.
Hypertrophic scars are still a major burden for numerous patients, especially after burns. Many treatment options are available; however, no evidence‐based treatment protocol is available with ...recommendations mostly emerging from experience or lower quality studies. This review serves to discuss the currently available literature. A systematic review was performed and the databases PubMed and Web of Science were searched for suitable publications. Only original articles in English that dealt with the treatment of hypertrophic scars in living humans were analyzed. Further, studies with a level of evidence lower than 1 as defined by the American Society of Plastic Surgeons were excluded. After duplicate exclusion, 1638 studies were screened. A qualitative assessment yielded 163 articles eligible for evidence grading. Finally nine studies were included. Four of them used intralesional injections, four topical therapeutics and one assessed the efficacy of CO2‐laser. Intralesional triamcinolone + fluorouracil injections, and topical pressure and/or silicone therapy revealed significant improvements in terms of scar height, pliability, and pigmentation. This systematic review showed that still few high‐quality studies exist to evaluate therapeutic means and their mechanisms for hypertrophic scars. Among these, most of them assessed the efficacy of intralesional triamcinolone injections with the same treatment protocol. Intralesional injection appears to be the best option for hypertrophic scar treatment. Future studies should focus on a possible optimization of infiltrative therapies, consistent end‐point evaluations, adequate follow‐up periods, and possibly intraindividual treatments.
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