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Abstract The transcription factor FOXP3 is essential for the development and function of CD4+CD25hiFOXP3+ regulatory T (Treg) 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 Treg cells, which may provide the missing link toward a better molecular definition of the regulatory phenotype. Reviewers: Dr Jim Di Danto, Dr Benedita Rocha and Dr Werner Solbach.

Abstract 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. Two AA patients were additionally analyzed after achieving a partial remission following immunosuppression. The regulation of selected candidate genes was confirmed by real-time RT-PCR. Results Among more than 22.200 transcripts, 583 genes were differentially expressed in the bone marrow of AA patients compared to healthy controls. Dysregulated genes are involved in T-cell mediated cytotoxicity, immune response of Th1 differentiated T-cells, and major regulators of immune function. In hematological remission the expression levels of several candidate genes tend to normalize, such as immune regulators and genes involved in proinflammatory immune response. Conclusion Our study suggests a pivotal role of Th1/Tc1 differentiated T-cells in immune-mediated marrow destruction of AA patients. Most importantly, immune regulatory genes could be identified, which are likely involved in the recovery of hematopoiesis and may help to design new therapeutic strategies in bone marrow failure syndromes.

The article by Faal et al. [1] describes differences in the level of FOXP3 mRNA expression in the conjunctiva of patients with Chlamydia trachomatis infection. The authors suggest that their [...]

A letter to the editor is presented in response to the article about conjunctival FOXP3 expression in trachoma by N. Faal, R. L. Bailey, D. Jeffries, H. Joof, I. Sarr in the previous issue.

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. Pathogen characterization is accompanied by an antimicrobial susceptibility test (with S-I-R classification), which deserves special attention, especially in the context of ABS. All of these aspects are dealt with in this work and represented using two practical examples of urinary and bloodstream diagnostics that are relevant for outpatients and inpatients., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

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. The main indications for the new substances are therefore infections with multi-resistant gram-negative bacteria.In clinical use, it should be noted that the BLI does not close efficacy gaps in the β-lactam/BLI combination (e.g. no effect of cephalosporin/BLI combinations on anaerobes or enterococci).Cefiderocol is the first representative of the siderophore cephalosporin antibiotic group to enter phase II clinical testing.Eravacyclin (tetracycline derivative) and plazomicin (aminoglycoside) are new non-β-lactam antibiotics in advanced clinical testing (phase III).In order to maintain the efficacy of new reserve antibiotics for as long as possible, a prescription should only be made if an additional benefit in comparison to established substances has been proven, e.g. by a resistance test., Competing Interests: Die Autoren erklären, dass für die letzten 3 Jahre beim Erstautor (MPK) keine Interessenkonflikte bestehen. Der Zweitautor (GG) hat in diesem Zeitraum Vortragshonorare der Firmen Astra-Zenecka, BioMerieux, MSD und Roche erhalten., (Georg Thieme Verlag KG Stuttgart · New York.)

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. This distinct population of induced TR cells express neither CD25 nor the TR-associated transcription factor Foxp3. Strikingly, CD25 is not even up-regulated upon stimulation. Despite the lack in Foxp3 expression, these in vivo-induced CD25- TR cells are able to interfere with an Ag-specific CD8+ T cell-mediated intestinal inflammation without significant increase in CD25 and Foxp3 expression. Thus, our results demonstrate that in vivo-induced Ag-specific TR cells represent a distinct population of Foxp3-CD25- TR cells with regulatory capacity both in vitro and in vivo.

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. Nrp1, a receptor involved in axon guidance, angiogenesis, and the activation of T cells, is constitutively expressed on the surface of CD4+CD25+ Treg cells independently of their activation status. In contrast, Nrp1 expression is down-regulated in naive CD4+CD25- T cells after TCR stimulation. Furthermore, CD4+Nrp1(high) T cells express high levels of Foxp3 and suppress CD4+CD25- T cells. Thus, Nrp1 constitutes a useful surface marker to distinguish Treg cells from both naive and recently activated CD4+CD25+ non-regulatory T cells.