Presence of hypervirulence-associated determinants in Klebsiella pneumoniae from hospitalised patients in Germany.

Background: Klebsiella (K.) pneumoniae is a ubiquitous Gram-negative bacterium and a common coloniser of animals and humans. Today, K.

[Diagnostic stewardship in outpatient and hospital medicine with focus on microbiological urinary and bloodstream diagnostics].

Targeted infection diagnosis supports decision-making in the rational use of antibiotics usually encompassed as Antibiotic Stewardship (ABS). Similar to ABS, the term "Diagnostic Stewardship" (DGS) is suggested, whereas DGS includes, beneath general, predominantly microbiological infection diagnostics - with specific pathogen detection, conventional via culture or immunology, increasingly also using molecular biological methods. Especially in microbiology, pre-analytics, analytics and post-analytics play an essential role.

[New Antibiotics for Treatment of Highly Resistant Gram-negative Bacteria].

New β-lactam/β-lactamase inhibitor (BLI) combinations (ceftolozan/tazobactam, ceftazidim/avibactam, meropenem/vaborbactam, imipenem/relebactam, aztreonam/avibactam) are the focus of newly approved antibiotics or those currently in advanced clinical testing. In contrast to the BLI currently available, the new inhibitors avibactam, vaborbactam and relebactam are not structurally β-lactams.The combination with a BLI protects β-lactam from degradation by broad-spectrum β-lactamases from gram-negative pathogens.

Impact of 5-aza-2'-deoxycytidine and epigallocatechin-3-gallate for induction of human regulatory T cells.

The epigenetic regulation of transcription factor genes is critical for T-cell lineage specification. A specific methylation pattern within a conserved region of the lineage specifying transcription factor gene FOXP3, the Treg-specific demethylated region (TSDR), is restricted to regulatory T (Treg) cells and is required for stable expression of FOXP3 and suppressive function. We analysed the impact of hypomethylating agents 5-aza-2'-deoxycytidine and epigallocatechin-3-gallate on human CD4(+)  CD25(-) T cells for generating demethylation within FOXP3-TSDR and inducing functional Treg cells.

Quantification of regulatory T cells in septic patients by real-time PCR-based methylation assay and flow cytometry.

During sepsis, a relative increase of regulatory T (Treg) cells has been reported. Its persistence is associated with lymphocyte anergy, immunoparalysis and a poor prognosis. Currently, an exact quantification of human Treg cells based on protein expression of marker molecules is ambiguous, as these molecules are expressed also by activated non-regulatory T cells.

PLAU inferred from a correlation network is critical for suppressor function of regulatory T cells.

Human FOXP3(+)CD25(+)CD4(+) regulatory T cells (Tregs) are essential to the maintenance of immune homeostasis. Several genes are known to be important for murine Tregs, but for human Tregs the genes and underlying molecular networks controlling the suppressor function still largely remain unclear. Here, we describe a strategy to identify the key genes directly from an undirected correlation network which we reconstruct from a very high time-resolution (HTR) transcriptome during the activation of human Tregs/CD4(+) T-effector cells.

First insight into the kinome of human regulatory T cells.

Regulatory T cells (Tregs) are essential for controlling peripheral tolerance by the active suppression of various immune cells including conventional T effector cells (Teffs). Downstream of the T cell receptor (TCR), more than 500 protein kinases encoded by the human genome have to be considered in signaling cascades regulating the activation of Tregs and Teffs, respectively. Following TCR engagement, Tregs posses a number of unique attributes, such as constitutive expression of Foxp3, hyporesponsiveness and poor cytokine production.

FOXP3 Expression in GARP-Transduced Helper T Cells Is Not Associated with FOXP3 TSDR Demethylation.

AIM: Glycoprotein A repetitions predominant (GARP or LRRC32) represents a human regulatory CD4+ CD25(hi) FOXP3+ T (T(reg)) cell-specific receptor that controls FOXP3. Ectopic expression of GARP in helper T (T(h)) cells has been shown to be sufficient for the induction of FOXP3 and generation of a stable regulatory phenotype. Since expression of FOXP3 in Treg cells is epigenetically controlled by a conserved motif, the so-called T(reg)-specific demethylated region (TSDR), we asked whether GARP-mediated upregulation of FOXP3 in Th cells is similarly accompanied by demethylation of the TSDR.

FOXP3 and GARP (LRRC32): the master and its minion.

The transcription factor FOXP3 is essential for the development and function of CD4+CD25hiFOXP3+ regulatory T (T(reg)) cells, but also expressed in activated human helper T cells without acquisition of a regulatory phenotype. This comment focuses on glycoprotein-A repetitions predominant (GARP or LRRC32) recently identified as specific marker of activated human T(reg) cells, which may provide the missing link toward a better molecular definition of the regulatory phenotype.

Perspectives on Regulatory T Cell Therapies.

Adoptive transfer in animal models clearly indicate an essential role of CD4+ CD25+ FOXP3+ regulatory T (T(reg)) cells in prevention and treatment of autoimmune and graft-versus-host disease. Thus, T(reg) cell therapies and development of drugs that specifically enhance T(reg) cell function and development represent promising tools to establish dominant tolerance. So far, lack of specific markers to differentiate human T(reg) cells from activated CD4+ CD25+ effector T cells, which also express FOXP3 at different levels, hampered such an approach.

CD83 expression in CD4+ T cells modulates inflammation and autoimmunity.

The transmembrane protein CD83 has been initially described as a maturation marker for dendritic cells. Moreover, there is increasing evidence that CD83 also regulates B cell function, thymic T cell maturation, and peripheral T cell activation. Herein, we show that CD83 expression confers immunosuppressive function to CD4(+) T cells.

Chronic antigen stimulation in vivo induces a distinct population of antigen-specific Foxp3 CD25 regulatory T cells.

The concept of immune regulation/suppression has been well-established and, besides thymus-derived CD4+CD25+ regulatory T (TR) cells, it became clear that a variety of additional peripherally induced TR cells play vital roles in protection from many harmful immune responses including intestinal inflammation. In the present study, we have analyzed in vivo-induced Ag-specific CD4+ TR cells with respect to their molecular and functional phenotype. By comparative genomics we could show that these Ag-specific TR cells induced by chronic Ag stimulation in vivo clearly differ in their genetic program from naturally occurring thymus-derived CD4+CD25+ TR cells.

Identification of novel regulators in T-cell differentiation of aplastic anemia patients.

Background: Aplastic anemia (AA) is a bone marrow failure syndrome mostly characterized by an immune-mediated destruction of marrow hematopoietic progenitor/stem cells. The resulting hypocellularity limits a detailed analysis of the cellular immune response. To overcome this technical problem we performed a microarray analysis of CD3+ T-cells derived from bone marrow aspirates and peripheral blood samples of newly diagnosed AA patients and healthy volunteers.

Signatures of human regulatory T cells: an encounter with old friends and new players.

Background: Naturally occurring CD4+ CD25+ regulatory T cells (TReg) are involved in the control of autoimmune diseases, transplantation tolerance, and anti-tumor immunity. Thus far, genomic studies on TReg cells were restricted to murine systems, and requirements for their development, maintenance, and mode of action in humans are poorly defined.

Results: To improve characterization of human TReg cells, we compiled a unique microarray consisting of 350 TReg cell associated genes (Human TReg Chip) based on whole genome transcription data from human and mouse TReg cells.

UBD, a downstream element of FOXP3, allows the identification of LGALS3, a new marker of human regulatory T cells.

Here, we report the identification of the ubiquitin-like gene UBD as a downstream element of FOXP3 in human activated regulatory CD4(+)CD25(hi) T cells (T(reg)). Retroviral transduction of UBD in human allo-reactive effector CD4(+) T helper (T(h)) cells upregulates CD25 and mediates downregulation of IL4 and IL5 expression similar to overexpression of FOXP3. Moreover, UBD impairs T(h) cell proliferation without upregulation of FOXP3 and impairs calcium mobilization.

1alpha,25-Dihydroxyvitamin D3 is a potent suppressor of interferon gamma-mediated macrophage activation.

1alpha,25-Dihydroxyvitamin D3 (1alpha,25(OH)2D3), the activated vitamin D3 hormone, is a key regulator of calcium homeostasis and thereby indispensable for bone metabolism. In addition, 1alpha,25(OH)2D3 is known to mediate predominantly immunosuppressive responses in vitro and in vivo. It has been demonstrated that macrophages can produce 1alpha,25(OH)2D3 on activation with interferon gamma (IFN-gamma), although little is understood about the biologic significance of this response.

Conformational restraints and flexibility of 14-meric peptides in complex with HLA-B*3501.

Human HLA-B*3501 binds an antigenic peptide of 14-aa length derived from an alternative reading frame of M-CSF with high affinity. Due to its extraordinary length, the exact HLA binding mode was unpredictable. The crystal structure of HLA-B*3501 at 1.

Neuropilin-1: a surface marker of regulatory T cells.

CD4+CD25+ regulatory T cells (Treg cells) control immune responsiveness to a large variety of antigens. The isolation and therapeutic manipulation of Treg cells requires the use of reliable surface receptors that are selectively up-regulated in Treg cells. On the basis of global gene expression studies, we identified neuropilin-1 (Nrp1) as a specific surface marker for CD4+CD25+ Treg cells.

Changes in actin dynamics at the T-cell/APC interface: implications for T-cell anergy?

Over the past 20 years the role of the actin cytoskeleton in the formation of the immunological synapse and in T-cell activation has been the subject of intense scrutiny. T-cell receptor (TCR) signaling leads to tyrosine phosphorylation of numerous adapter proteins whose function is to relay signals to downstream components of the TCR signaling pathway and, in particular, to molecules implicated in remodeling the actin cytoskeleton. Here, we discuss how signals from the TCR converge on two key regulators of the actin cytoskeleton, Ena/vasodilator-stimulated phosphoproteins (VASPs) and the actin-related protein (ARP2/3) complex.