In this issue

Abstract Cover image The cover shows human monocyte‐derived macrophages migrating into gelled collagen I using the mesenchymal migration mode as described by Maridonneau–Parini and colleagues in their review ( pp . 2805–2813). At the tip of the cell protrusions, 3D podosomes form and there is an elongated and protrusive cell shape, which is characteristic of this migration mode. The macrophages were fixed, permeabilized and stained with phalloidin for F‐actin (green) and show accumulation of F‐actin at the 3D podosomes; DAPI staining identifies the nuclei (blue). The image is a projection of five z ‐sections of 0.4 μm, obtained by confocal microscopy and was provided by Véronique Le Cabec. “CYLDing” T‐cell development from aberrant NF‐κB activation Thymocyte development is a process regulated by networks of signaling pathways and transcription factors. An understanding of the delicate regulation and interactions between these networks during thymic development remains largely elusive. The functional deubiquitinating enzyme CYLD, which is a negative regulator of NF‐κB and MAPK pathways, has previously been shown to be required for thymocyte positive selection. In this issue, Tsagaratou et al. demonstrate that thymocyte selection depends on the ability of CYLD to prevent the aberrant activation of NF‐κB in an IKK2‐dependent manner. Whereas inactivation of CYLD severely compromises the selection of single‐positive thymocytes, concomitant inactivation of IKK2 rescues the developmental defects of CYLD‐deficient double‐positive thymocytes. Furthermore, the authors find an IKK2‐independent role for CYLD in establishing physiological populations of CD4 + and CD8 + T cells in peripheral lymphoid tissues. This study establishes a critical role for CYLD in safeguarding the threshold of IKK2‐dependent activation of NF‐κB for thymocyte selection. pp. 3054–3062How Salmonella stops diabetes The hygiene hypothesis suggests that, in the developed world, decreased exposure to chronic infections contributes toward an increased incidence of allergy or autoimmunity. In this issue, Newland et al. investigate the mechanism behind the protective effect of Salmonella typhimurium on type 1 diabetes in the NOD mouse model. The authors demonstrate that persistent exposure to the bacterium does not induce elevated numbers of Foxp3 + regulatory T (Treg) cells, and partial depletion of Treg cells with cyclophosphamide does not break Salmonella ‐induced protection against diabetes. A sustained alteration of the dendritic cell population in Salmonella ‐infected NOD mice is due to the upregulation of a number of transcripts, including the co‐inhibitory receptor PD‐L1. PD‐L1 expression on DCs is elevated throughout Salmonella infection and antibody blocking of the PD‐L1 receptor is sufficient to reverse Salmonella ‐induced diabetes protection. These findings highlight the how complex interplay between genetic susceptibility and the infectious environment contribute to the pervasiveness of autoimmune diseases. pp. 2966–2976Triggering CLEC‐2 in myeloid cells amplifies IL‐10 production C‐type lectin receptors (CLRs) regulate many myeloid cell functions, such as phagocytosis, inflammation, and activation of T and B cells. CLEC‐2 is a CLR that has been primarily characterized in platelets, where it signals to promote aggregation. In this issue, Mourão‐Sá et al. use a new anti‐CLEC‐2 monoclonal antibody (mAb) to show that CLEC‐2 is additionally expressed by macrophages and dendritic cells (DCs) and that its expression is increased by inflammatory signals. mAb‐mediated cross‐linking of CLEC‐2 in myeloid cells leads to a Syk‐ and NFAT‐dependent increase in IL‐10 production triggered by LPS. Moreover, co‐administration of anti‐CLEC‐2 mAb and LPS to mice leads to increased serum levels of IL‐10 in a mechanism dependent on DCs and macrophages. Overall, these data suggest a role for myeloid cells expressing CLEC‐2 in the modulation of inflammatory responses. pp. 3040–3053Cholera toxin adjuvanticity in ear immunization is dependent on DC migration The skin is an attractive site for immunization. In this issue, Meza‐Sánchez et al. examine the potential of Cholera Toxin (CT) and its non‐toxic β subunit (CTB) as adjuvants in ear immunization. Intradermal immunization in the ear with model antigens adjuvanted with either CT or CTB induces local DC activation with the production of TGF‐β, followed by efficient antigen presentation and the production of IFN‐γ and IL‐17 by CD4 + T cells in the draining lymph nodes. Immunization with CT or with CTB leads to the induction of a sustained IL‐17‐ and IFN‐α‐dependent delayed‐type hypersensitivity (DTH) response in the ear, which is also dependent on the presence of migrating skin DCs. These results indicate that the strong potential of CTB as an adjuvant in ear immunization is dependent on DC activation and migration. pp. 2894–2904From our sister journals – A better way of detecting histone methylations High‐throughput genomic sequencing and quantitative mass spectrometry (MS)‐based proteomics are two powerful but expensive techniques that are often applied separately. However, Stunneberg and Vermeulen have applied the techniques in combination, reiteratively in the context of epigenetics research. In particular, they studied the biology of lysine trimethylations on the N‐terminus of histone H3 and H4 that are associated with different functional states of chromatin. Furthermore, they give a nice overview of the state of the art and of the challenges of these two techniques. With high‐throughput sequencing‐based techniques one can, among other things, look for genomic‐binding sites of a particular protein. MS‐based techniques on the other hand can be used to identify thousands of proteins in complex lysates or subfractions and it can also help to identify interaction partners of a given protein.