Resident-Memory T Cells in Tissue-Restricted Immune Responses: For Better or Worse?

Tissue-resident-memory CD8+ T cells (TRM) have been described as a non-circulating memory T cell subset that persists at sites of previous infection. While TRM in all non-lymphoid organs probably share a core signature differentiation pathway, certain aspects of their maintenance and effector functions may vary. It is well-established that TRM provide long-lived protective immunity through immediate effector function and accelerated recruitment of circulating immune cells. Besides immune defense against pathogens, other immunological roles of TRM are less well-studied. Likewise, evidence of a putative detrimental role of TRM for inflammatory diseases is only beginning to emerge. In this review, we discuss the protective and harmful role of TRM in organ-specific immunity and immunopathology as well as prospective implications for immunomodulatory therapy

Nogo receptor is involved in the adhesion of dendritic cells to myelin

BACKGROUND: Nogo-66 receptor NgR1 and its structural homologue NgR2 are binding proteins for a number of myelin-associated inhibitory factors. After neuronal injury, these inhibitory factors are responsible for preventing axonal outgrowth via their interactions with NgR1 and NgR2 expressed on neurons. In vitro, cells expressing NgR1/2 are inhibited from adhering to and spreading on a myelin substrate. Neuronal injury also results in the presence of dendritic cells (DCs) in the central nervous system, where they can come into contact with myelin debris. The exact mechanisms of interaction of immune cells with CNS myelin are, however, poorly understood. METHODS: Human DCs were differentiated from peripheral blood monocytes and mouse DCs were differentiated from wild type and NgR1/NgR2 double knockout bone marrow precursors. NgR1 and NgR2 expression were determined with quantitative real time PCR and immunoblot, and adhesion of cells to myelin was quantified. RESULTS: We demonstrate that human immature myeloid DCs express NgR1 and NgR2, which are then down-regulated upon maturation. Human mature DCs also adhere to a much higher extent to a myelin substrate than immature DCs. We observe the same effect when the cells are plated on Nogo-66-His (binding peptide for NgR1), but not on control proteins. Mature DCs taken from Ngr1/2 knockout mice adhere to a much higher extent to myelin compared to wild type mouse DCs. In addition, Ngr1/2 knockout had no effect on in vitro DC differentiation or phenotype. CONCLUSIONS: These results indicate that a lack of NgR1/2 expression promotes the adhesion of DCs to myelin. This interaction could be important in neuroinflammatory disorders such as multiple sclerosis in which peripheral immune cells come into contact with myelin debris

SatSel: A Satellite Selection Algorithm to reduce delivery time in DTN-Nanosatellite Networks for Internet Access in Rural Areas.

There are some different ways to connect rural areas to the Internet. One of these provides the use of a nanosatellite constellation. This type of network allows people in rural areas to enjoy all services the Internet can offer keeping low the cost of Internet access. One of the critical aspect is related to the delivery time, because LEO satellite links are not always up. This means that the system must be able to deal with periodic disruptions and high delays in the path from the source to the destination, considering that data could be stored in nanosatellite, Internet gateway (also called hot spot), and rural gateway (also called cold spot) buffers also for several seconds or minutes waiting to be forwarded. In the path from rural areas to the Internet, it is possible to reduce data delivery time acting on rural gateways. We propose SatSel: a selection algorithm which allows the cold spots to choose the nanosatellite to whom upload data in order to reduce the data delivery tim

Neutrophils in cancer: neutral no more

Neutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view. The traditionally held belief that neutrophils are inert bystanders is being challenged by the recent literature. Emerging evidence indicates that tumours manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumour behaviour. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets

A multi-targeted approach to suppress tumor-promoting inflammation

Cancers harbor significant genetic heterogeneity and patterns of relapse following many therapies are due to evolved resistance to treatment. While efforts have been made to combine targeted therapies, significant levels of toxicity have stymied efforts to effectively treat cancer with multi-drug combinations using currently approved therapeutics. We discuss the relationship between tumor-promoting inflammation and cancer as part of a larger effort to develop a broad-spectrum therapeutic approach aimed at a wide range of targets to address this heterogeneity. Specifically, macrophage migration inhibitory factor, cyclooxygenase-2, transcription factor nuclear factor-κB, tumor necrosis factor alpha, inducible nitric oxide synthase, protein kinase B, and CXC chemokines are reviewed as important antiinflammatory targets while curcumin, resveratrol, epigallocatechin gallate, genistein, lycopene, and anthocyanins are reviewed as low-cost, low toxicity means by which these targets might all be reached simultaneously. Future translational work will need to assess the resulting synergies of rationally designed antiinflammatory mixtures (employing low-toxicity constituents), and then combine this with similar approaches targeting the most important pathways across the range of cancer hallmark phenotypes

Common genetic polymorphisms within NFκB-Related genes and the risk of developing invasive aspergillosis

Invasive Aspergillosis (IA) is an opportunistic infection caused by Aspergillus, a ubiquitously present airborne pathogenic mold. A growing number of studies suggest a major host genetic component in disease susceptibility. Here, we evaluated whether 14 single-nucleotide polymorphisms within NF kappa B1, NF kappa B2, RelA, RelB, Rel, and IRF4 genes influence the risk of IA in a population of 834 high-risk patients (157 IA and 677 non IA) recruited through a collaborative effort involving the aspBlOmics consortium and four European clinical institutions. No significant overall associations between selected SNPs and the risk of IA were found in this large cohort. Although a hematopoietic stem cell transplantation (HSCT)-stratified analysis revealed that carriers of the IRF4(rs12203592T/T) genotype had a six-fold increased risk of developing the infection when compared with those carrying the C allele (ORREC = 6.24, 95%CI 1.25-31.2, P = 0.026), the association of this variant with IA risk did not reach significance at experiment-wide significant threshold. In addition, we found an association of the IRF4(AATC) and IRF4(GGTC) haplotypes (not including the IRF4(rs12203592T/T) risk allele) with a decreased risk of IA but the magnitude of the association was similar to the one observed in the single-SNP analysis, which indicated that the haplotypic effect on IA risk was likely due to the IRF4(rs12203592) SNP Finally, no evidence of significant interactions among the genetic markers tested and the risk of IA was found. These results suggest that the SNPs on the studied genes do not have a clinically relevant impact on the risk of developing IA.- This study was supported by grants PI12/02688 from Fond de Investigaciones Sanitarias (Institute de Salud Carlos III, Madrid, Spain), the ERA-NET PathoGenoMics (03159000A; Ministerio de Ciencia e Innovation PIM2010EPA-00756, Madrid, Spain), the Collaborative Research Center / Transregio 124 FungiNet, the Austrian Science Fundation (FWF I-656-B09), the Fundacao para a Ciencia e Tecnologia (FCT), cofundcd by Programa Operacional Regional do Norte (ON.2-O Novo Norte), the Quadro de Referencia Estrategico Nacional (QREN) through the Fundo Europeu de Desenvolvimento Regional (FEDER) and the Projeto Estrategico - LA 26 - 2013-2014 (PEst-C/SAU/LA0026/2013). Agostinho Carvalho and Cristina Cunha were supported by the Fundacao para a e Tecnologia (FCT), Portugal (IF/00735/2014 and SFRH/BPD/96176/2013, respectively). The PCRAGA trial was supported by an unrestricted grant from Pfizer, which had no involvement or control over the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the paper for publication. This study was also supported by Astellas Pharma Inc. and a donation from Consuelo Gonzalez Moreno, an acute myeloid leukemia survivor.info:eu-repo/semantics/publishedVersio

Nogo-Receptors NgR1 and NgR2 Do Not Mediate Regulation of CD4 T Helper Responses and CNS Repair in Experimental Autoimmune Encephalomyelitis

Myelin-associated inhibition of axonal regrowth after injury is considered one important factor that contributes to regeneration failure in the adult central nervous system (CNS). Blocking strategies targeting this pathway have been successfully applied in several nerve injury models, including experimental autoimmune encephalomyelitis (EAE), suggesting myelin-associated inhibitors (MAIs) and functionally related molecules as targets to enhance regeneration in multiple sclerosis. NgR1 and NgR2 were identified as interaction partners for the myelin proteins Nogo-A, MAG and OMgp and are probably mediating their growth-inhibitory effects on axons, although the in vivo relevance of this pathway is currently under debate. Recently, alternative functions of MAIs and NgRs in the regulation of immune cell migration and T cell differentiation have been described. Whether and to what extent NgR1 and NgR2 are contributing to Nogo and MAG-related inhibition of neuroregeneration or immunomodulation during EAE is currently unknown. Here we show that genetic deletion of both receptors does not promote functional recovery during EAE and that NgR1 and NgR2-mediated signals play a minor role in the development of CNS inflammation. Induction of EAE in Ngr1/2-double mutant mice resulted in indifferent disease course and tissue damage when compared to WT controls. Further, the development of encephalitogenic CD4+ Th1 and Th17 responses was unchanged. However, we observed a slightly increased leukocyte infiltration into the CNS in the absence of NgR1 and NgR2, indicating that NgRs might be involved in the regulation of immune cell migration in the CNS. Our study demonstrates the urgent need for a more detailed knowledge on the multifunctional roles of ligands and receptors involved in CNS regeneration failure

Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci.

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct signal mapped predominantly to noncoding sequence, implying that association with T2D is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine mapping implicated rs10830963 as driving T2D association. We confirmed that the T2D risk allele for this SNP increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease