European Journal of Immunology

The lymph node (LN) is home to resident macrophage populations that are essential for immune function and homeostasis, but key factors controlling this niche are undefined. Here we show that fibroblastic reticular cells (FRCs) are an essential component of the LN macrophage niche. Genetic ablation of FRCs caused rapid loss of macrophages and monocytes from LNs across two in vivo models. Macrophages co-localised with FRCs in human LNs, and murine single-cell RNA-sequencing revealed that FRC subsets broadly expressed master macrophage regulator CSF1...

Similar to immune cells, non-hematopoietic cells recognize microbial and endogenous threats. Their response to these stimuli is dependent on the environmental context. For example, intact intestinal epithelium expresses pattern recognition receptors (PRRs) but should tolerate commensal bacteria, while damaged epithelium should respond promptly to initiate an immune response. This indicates that non-hematopoietic cells possess mechanisms to sense environmental context and to regulate their responses. Inhibitory receptors provide context sensing to immune cells...

Polyphosphates are highly conserved, linear polymers of monophosphates that reside in all living cells. Bacteria produce long chains containing hundreds to thousands of phosphate units, which can interfere with host defense to infection. Here, we report that intratracheal long-chain polyphosphate administration to C57BL/6J mice resulted in the release of proinflammatory cytokines and influx of Ly6G+ polymorphonuclear neutrophils in the bronchoalveolar lavage fluid causing a disruption of the physiologic endothelial-epithelial small airway barrier and histologic signs of lung injury...

Vγ9Vδ2 T cells can recognise various molecules associated with cellular stress or transformation, providing a unique avenue for the treatment of cancers or infectious diseases. Nonetheless, Vγ9Vδ2 T cell-based immunotherapies frequently achieve suboptimal efficacies in vivo. Enhancing the cytotoxic effector function of Vγ9Vδ2 T cells is one potential avenue through which the immunotherapeutic potential of this subset may be improved. We compared the use of four pro-inflammatory cytokines on the effector phenotype and functions of in vitro expanded Vγ9Vδ2 T cells, and demonstrate TCR-independent cytotoxicity mediated through CD26, CD16, and NKG2D which could be further enhanced by IL-23, IL-18, and IL-15 stimulation throughout expansion...

Antigen presenting cells (APCs) are critical cells bridging innate and adaptive immune responses by taking up, processing, and presenting antigens to naïve T cells. At steady state, APCs thus control both tissue homeostasis and the induction of tolerance immune responses. In allergies however, APCs drive a Th2-biased immune response that is directed against otherwise harmless antigens from the environment. The main types of APCs involved in the induction of allergy are dendritic cells, monocytes and macrophages...

Mast cells (MCs) are immune cells residing in tissues and playing indispensable roles in maintaining homeostasis and inflammatory states. Skin lesions associated with atopic dermatitis (AD) and type 2 skin inflammation display an increment in MCs, which have both pro- and anti-inflammatory effects. The direct and indirect activation of skin MCs by environmental factors such as S. aureus can instigate type 2 skin inflammation in AD with poorly understood mechanisms. Furthermore, both IgE-dependent and -independent degranulation of MCs contribute to pruritus in AD...

Tauopathies, which include frontotemporal dementia, Alzheimer's disease, and chronic traumatic encephalopathy, are a class of neurological disorders resulting from pathogenic tau aggregates. These aggregates disrupt neuronal health and function leading to the cognitive and physical decline of tauopathy patients. Genome-wide association studies and clinical evidence have brought to light the large role of the immune system in inducing and driving tau-mediated pathology. More specifically, innate immune genes are found to harbor tauopathy risk alleles and innate immune pathways are upregulated throughout the course of disease...

Asthma is classically considered to be a disease of type 2 immune dysfunction, since many patients exhibit the consequences of excess secretion of cytokines such as IL-4, IL-5 and IL-13 concomitant with inflammation typified by eosinophils. Mouse and human disease models have determined that many of the canonical pathophysiologic features of asthma may be caused by these disordered type 2 immune pathways. As such considerable efforts have been made to develop specific drugs targeting key cytokines. There are currently available multiple biologic agents that successfully reduce the functions of IL-4, IL-5 and IL-13 in patients, and many improve the course of severe asthma...

Granulocytes provide a fast innate response to pathogens and allergens. In allergy and anti-helminth immunity, epithelial cells of damaged barriers release alarmins like IL-25, IL-33 and TSLP but also chemokines like CXCL1 or CCL11 to promote cell recruitment and inflammation. In addition, mast cells positioned at barrier tissue sites also quickly release mediators upon specifically sensing antigens through IgE bound to FcεR1 on their surface. Released mediators induce the recruitment of different granulocytes in a timely ordered manner...

Birth prior to 37 completed weeks of gestation is referred to as preterm (PT). Premature newborns are at increased risk of developing infections as neonatal immunity is a developing structure. Monocytes, which are key players after birth, activate inflammasomes. Investigations into the identification of innate immune profiles in premature compared to full term infants are limited. Our research includes the investigation of monocytes and NK cells, gene expression and plasma cytokine levels to investigate any potential differences among a cohort of 68 healthy pre and full term infants...

γδT-cells are produced in the thymus throughout life, and provide immunity at epithelial-rich sites. Unlike conventional αβT-cells, γδT-cell development involves intrathymic acquisition of effector function, with priming for either IL17 or IFNγ production occurring during embryonic or adult life, respectively. How the thymus controls effector primed γδT-cell generation in adulthood is poorly understood. Here, we distinguished de novo γδT-cells from those undergoing thymus recirculation and/or retention using Rag2GFP mice alongside markers of maturation/effector priming including CD24, CD25, CD73 and IFNγ, the latter by crossing with IFNγYFP GREAT mice...

Extracellular vesicles (EVs) function as mediators of intercellular communication and as such influence the recipient cell function. EVs derived from immune cells can carry out many of the same functions as their parental cells, as they carry costimulatory molecules, antigens, and antigen-MHC complexes. As a result, there is a strong interest in understanding the composition and origin of immune cell derived EVs in order to understand their role in the pathogenesis of diseases. This study aimed to optimise methodologies to study immune cell derived EVs...

Due to ontogenetic changes in B cell developmental lineages, the mature B cell compartment constitutes by functionally different B cell subsets that emerged from prenatal, early postnatal or adult precursors. While negative selection processes operate primarily within the framework of B cell tolerance checkpoints during B cell development, further differentiation into distinct B cell subsets is additionally induced by positive selection. In addition to endogenous antigens, contact with microbial antigens is also involved in this selection process, with intestinal commensals having a significant influence on the development of a large layer within the B cell compartment...

Reexposure to a pathogen triggers the activation of memory T cells that have already encountered a similar microbe. These long-lived CD4 T cells either circulate through the blood and tissues or reside within organs and are referred to as tissue-resident T cells (CD4 TRM ). In the current issue of the European Journal of Immunology[Eur. J. Immunol. 2023.53:xxxx-xxxxx] issue, Curham et al. found that tissue-resident memory CD4 T cells in the lung and nasal tissues can respond to non-cognate immune challenges...

Regulatory T cells (Tregs) are essential for immune homeostasis and suppression of pathological autoimmunity but can also play a detrimental role in cancer progression via inhibition of anti-tumour immunity. Thus, there is broad applicability for therapeutic Treg targeting, either to enhance function, for example through adoptive cell therapy (ACT), or to inhibit function with small molecules or antibody-mediated blockade. For both of these strategies, the metabolic state of Tregs is an important consideration since cellular metabolism is intricately linked to function...

Diverse autoantibodies were suggested to contribute to severe outcomes of COVID-19, but their functional implications are largely unclear. ACE2, the SARS-CoV-2 receptor and a key regulator of blood pressure, was described to be one of many targets of autoantibodies in COVID-19. ACE2 in its soluble form (sACE2) is highly elevated in the blood of critically ill patients, raising the question of whether sACE2:spike complexes induce ACE2 reactivity. Screening 247 COVID-19 patients, we observed elevated sACE2 and anti-ACE2 IgG that poorly correlated...

Single cell RNA sequencing technologies have been successfully leveraged for immunological insights into human prenatal, paediatric and adult tissues. These single cell studies have led to breakthroughs in our understanding of stem, myeloid and lymphoid cell function. Computational analysis of fetal haematopoietic tissues has uncovered trajectories for T and B cell differentiation across multiple organ sites, and how these trajectories might be dysregulated in fetal and paediatric health and disease. As we enter the age of large-scale, multiomic and integrative single cell meta-analysis, we assess the advances and challenges of large-scale data generation, analysis and reanalysis, and data dissemination for a broad range of scientific and clinical communities...

Keratinocytes are pivotal cells in the pathogenesis of atopic dermatitis (AD) as much as Th2 cells. In this sense, regulation of pro-inflammatory features of keratinocytes might be useful for AD patients. P2X7R-mediated activation of NLRP3 inflammasome (N3I) in keratinocytes and myeloid cells plays crucial roles in AD. Nonetheless, inhibition of P2X7R has not been feasible because of polymorphisms and ubiquitous expression of P2X7R. Here, we report that GPCR19 colocalizes with P2X7R and a GPCR19 agonist (taurodeoxycholate, TDCA) inhibits the activation of P2X7R...

The skin and the oral mucosa represent interfaces to the environment that are constantly exposed to pathogens and harmless foreign antigens such as commensal bacteria. Both barrier organs share the presence of Langerhans cells (LC), distinctive members of the heterogeneous family of antigen-presenting dendritic cells (DC) that have the unique ability to promote tolerogenic as well as inflammatory immune responses. While skin LC have been extensively studied in the past decades, less is known about the function of oral mucosal LC...

Studies on the role of interleukins (ILs) in autoimmune and inflammatory diseases allow for the better understanding of pathologic mechanisms of disease and reshaping of treatment modalities. The development of monoclonal antibodies targeting specific ILs or IL signaling pathways (i.e. anti-IL-17/IL-23 in psoriasis or anti-IL-4/IL-13 in atopic dermatitis) is the shining example of therapeutic interventions in research. IL-21, belonging to the group of ɣc-cytokines (IL-2, IL-4, IL-7, IL-9, and IL-15), is gaining attention for its pleiotropic role in several types of immune cells as activator of various inflammatory pathways...