It is well established that tissue macrophages and tissue-resident memory CD8+ T cells (TRM) play important roles for pathogen sensing and rapid protection of barrier tissues. In contrast, the mechanisms by which these two cell types cooperate for homeostatic organ surveillance after clearance of infections is poorly understood. Here, we used intravital imaging to show that TRM dynamically followed tissue macrophage topology in noninflamed murine submandibular salivary glands (SMGs). Depletion of tissue macrophages interfered with SMG TRM motility and caused a reduction of interepithelial T cell crossing. In the absence of macrophages, SMG TRM failed to cluster in response to local inflammatory chemokines. A detailed analysis of the SMG microarchitecture uncovered discontinuous attachment of tissue macrophages to neighboring epithelial cells, with occasional macrophage protrusions bridging adjacent acini and ducts. When dissecting the molecular mechanisms that drive homeostatic SMG TRM motility, we found that these cells exhibit a wide range of migration modes: In addition to chemokine- and adhesion receptor–driven motility, resting SMG TRM displayed a remarkable capacity for autonomous motility in the absence of chemoattractants and adhesive ligands. Autonomous SMG TRM motility was mediated by friction and insertion of protrusions into gaps offered by the surrounding microenvironment. In sum, SMG TRM display a unique continuum of migration modes, which are supported in vivo by tissue macrophages to allow homeostatic patrolling of the complex SMG architecture.

Dendritic cells (DCs) are crucial for the priming of naive T cells and the initiation of adaptive immunity. Priming is initiated at a heterologous cell–cell contact, the immunological synapse (IS). While it is established that F-actin dynamics regulates signaling at the T cell side of the contact, little is known about the cytoskeletal contribution on the DC side. Here, we show that the DC actin cytoskeleton is decisive for the formation of a multifocal synaptic structure, which correlates with T cell priming efficiency. DC actin at the IS appears in transient foci that are dynamized by the WAVE regulatory complex (WRC). The absence of the WRC in DCs leads to stabilized contacts with T cells, caused by an increase in ICAM1-integrin–mediated cell–cell adhesion. This results in lower numbers of activated and proliferating T cells, demonstrating an important role for DC actin in the regulation of immune synapse functionality.

Allergic asthma is a chronic inflammatory remitting-relapsing disease affecting the airways. Long-lived allergen-specific memory CD4 + T helper 2 (Th2) cells in mice persist in lungs for more than 2 years after the induction of experimental allergic asthma (EAA). To further understand lung Th2 memory cells, we tracked CD4 + T cells in spleen and lungs from healthy mice, through the initiation of acute EAA, recovery (remission), and allergen-induced disease relapse. We identified a lung CD3 + CD4 + cell subset that expresses CD44 hi CD62L − CD69 + ST2 + , produces Th2 cytokines, and mediates allergen-induced disease relapse despite treatment with FTY720 and anti-CD4 antibody. These cells reside in the lung tissue for the lifetime of mice (>665 days) and represent long-lived pathogenic Th2 tissue resident memory cells (T RMs ) that maintain “allergic memory” in lung. We speculate that these data implicate that human Th2-T RMs sentinels in lungs of patients are poised to rapidly respond to inhaled allergen and induce asthma attacks and that therapeutic approaches targeting these cells may provide relief to patients with allergic asthma.

Long non-coding RNAs (lncRNAs) are non-protein coding transcripts that modulate mRNA and microRNA (miRNA) expression, thereby controlling multiple cellular processes, including transcriptional regulation of gene expression, cell differentiation and apoptosis. Ionizing radiation (IR), a strong cellular stressor, is known to influence gene expression of irradiated cells, mainly by activation of oxidative processes. Whether and how IR also affects lncRNA expression in human peripheral blood mononuclear cells (PBMCs) is still poorly understood. Exposure of PBMCs to IR dose-dependently activated p53 and its downstream target p21, ultimately leading to cell-cycle arrest and/or apoptosis. Cleavage of caspase-3, a specific process during apoptotic cell death, was detectable at doses as low as 30 Gy. Transcriptome analysis of 60 Gy–irradiated PBMCs revealed a strong time-dependent regulation of a variety of lncRNAs. Among many unknown lncRNAs we also identified a significant upregulation of Trp53cor1, MEG3 and TUG1, which have been shown to be involved in the regulation of cell cycle and apoptotic processes mediated by p53. In addition, we found 177 miRNAs regulated in the same samples, including several miRNAs that are known targets of upregulated lncRNAs. Our data show that IR dose-dependently regulates the expression of a wide spectrum of lncRNAs in PBMCs, suggesting a crucial role for lncRNAs in the complex regulatory machinery activated in response to IR.

AimsIschemic myocardial injury leads to the activation of inflammatory mechanisms and results in ventricular remodeling. Although great efforts have been made to unravel the molecular and cellular processes taking place in the ischemic myocardium, little is known about the effects on the surrounding tissue and other organs. The aim of this study was to determine region specific differences in the myocardium and in distant organs after experimental myocardial infarction by using a bioinformatics approach.Methods and ResultsA porcine closed chest reperfused acute myocardial infarction model and mRNA microarrays have been used to evaluate gene expression changes. Myocardial infarction changed the expression of 8903 genes in myocardial-, 856 in hepatic- and 338 in splenic tissue. Identification of myocardial region specific differences as well as expression profiling of distant organs revealed clear gene-regulation patterns within the first 24 hours after ischemia. Transcription factor binding site analysis suggested a strong role for Kruppel like factor 4 (Klf4) in the regulation of gene expression following myocardial infarction, and was therefore investigated further by immunohistochemistry. Strong nuclear Klf4 expression with clear region specific differences was detectable in porcine and human heart samples after myocardial infarction.ConclusionApart from presenting a post myocardial infarction gene expression database and specific response pathways, the key message of this work is that myocardial ischemia does not end at the injured myocardium. The present results have enlarged the spectrum of organs affected, and suggest that a variety of organ systems are involved in the co-ordination of the organism´s response to myocardial infarction.