Interleukin-7 (IL-7) is a critical cytokine in B- and T-lymphocyte development and maturation. Recent evidence suggests that IL-7 is a preferential homeostatic and survival factor for RORγt
innate T ...cells such as natural killer T (NKT) cells, γδT cells, and mucosal-associated invariant T (MAIT) cells in the periphery. Given the important contribution of these populations in antibacterial immunity at barrier sites, we questioned whether IL-7 could be instrumental in boosting the local host immune response against respiratory bacterial infection. By using a cytokine-monoclonal antibody approach, we illustrated a role for topical IL-7 delivery in increasing the pool of RORγt
IL-17A-producing innate T cells. Prophylactic IL-7 treatment prior to Streptococcus pneumoniae infection led to better bacterial containment, a process associated with increased neutrophilia and that depended on γδT cells and IL-17A. Last, combined delivery of IL-7 and α-galactosylceramide (α-GalCer), a potent agonist for invariant NKT (iNKT) cells, conferred an almost total protection in terms of survival, an effect associated with enhanced IL-17 production by innate T cells and neutrophilia. Collectively, we provide a proof of concept that IL-7 enables fine-tuning of innate T- cell functions. This might pave the way for considering IL-7 as an innovative biotherapeutic against bacterial infection.
Display omitted
Bacterial respiratory infections, either acute or chronic, are major threats to human health. Direct mucosal administration, through the airways, of therapeutic antibodies (Abs) ...offers a tremendous opportunity to benefit patients with respiratory infections. The mode of action of anti-infective Abs relies on pathogen neutralization and crystallizable fragment (Fc)-mediated recruitment of immune effectors to facilitate their elimination. Using a mouse model of acute pneumonia induced by Pseudomonas aeruginosa, we depicted the immunomodulatory mode of action of a neutralizing anti-bacterial Abs. Beyond the rapid and efficient containment of the primary infection, the Abs delivered through the airways harnessed genuine innate and adaptive immune responses to provide long-term protection, preventing secondary bacterial infection. In vitro antigen-presenting cells stimulation assay, as well as in vivo bacterial challenges and serum transfer experiments indicate an essential contribution of immune complexes with the Abs and pathogen in the induction of the sustained and protective anti-bacterial humoral response. Interestingly, the long-lasting response protected partially against secondary infections with heterologous P. aeruginosa strains. Overall, our findings suggest that Abs delivered mucosally promotes bacteria neutralization and provides protection against secondary infection. This opens novel perspectives for the development of anti-infective Abs delivered to the lung mucosa, to treat respiratory infections.
COVID-19 includes lung infection ranging from mild pneumonia to life-threatening acute respiratory distress syndrome (ARDS). Dysregulated host immune response in the lung is a key feature in ARDS ...pathophysiology. However, cellular actors involved in COVID-19-driven ARDS are poorly understood. Here, in blood and airways of severe COVID-19 patients, we serially analyzed unconventional T cells, a heterogeneous class of T lymphocytes (MAIT, γδT, and iNKT cells) with potent antimicrobial and regulatory functions. Circulating unconventional T cells of COVID-19 patients presented with a profound and persistent phenotypic alteration. In the airways, highly activated unconventional T cells were detected, suggesting a potential contribution in the regulation of local inflammation. Finally, expression of the CD69 activation marker on blood iNKT and MAIT cells of COVID-19 patients on admission was predictive of clinical course and disease severity. Thus, COVID-19 patients present with an altered unconventional T cell biology, and further investigations will be required to precisely assess their functions during SARS-CoV-2-driven ARDS.
is an opportunistic bacteria and a major cause of nosocomial pneumonia.
has many virulence factors contributing to its ability to colonize the host. LoxA is a lipoxygenase enzyme secreted by
that ...oxidizes polyunsaturated fatty acids. Based on previous
biochemical studies, several biological roles of LoxA have been hypothesized, including interference of the host lipid signaling, and modulation of bacterial invasion properties. However, the contribution of LoxA to
lung pathogenesis
remained unclear. In this study, we used complementary
and
approaches, clinical strains of
as well as lipidomics technology to investigate the role of LoxA in lung infection. We found that several
clinical isolates express LoxA. When secreted in the lungs, LoxA processes a wide range of host polyunsaturated fatty acids, which further results in the production of bioactive lipid mediators (including lipoxin A
). LoxA also inhibits the expression of major chemokines (e.g., MIPs and KC) and the recruitment of key leukocytes. Remarkably, LoxA promotes
persistence in lungs tissues. Hence, our study suggests that LoxA-dependent interference of the host lipid pathways may contribute to
lung pathogenesis.
CD1d-restricted invariant Natural Killer T (iNKT) cells represent a unique class of T lymphocytes endowed with potent regulatory and effector immune functions. Although these functions are acquired ...during thymic ontogeny, the sequence of events that gives rise to discrete effector subsets remains unclear. Using an unbiased single-cell transcriptomic analysis combined with functional assays, we reveal an unappreciated diversity among thymic iNKT cells, especially among iNKT1 cells. Mathematical modeling and biological methods unravel a developmental map whereby iNKT2 cells constitute a transient branching point toward the generation of iNKT1 and iNKT17 cells, which reconciles the two previously proposed models. In addition, we identify the transcription co-factor Four-and-a-half LIM domains protein 2 (FHL2) as a critical cell-intrinsic regulator of iNKT1 specification. Thus, these data illustrate the changing transcriptional network that guides iNKT cell effector fate.
Display omitted
•Unbiased scRNA-seq on thymic iNKT reveals discrete subsets in iNKT1 and iNKT2•Transcriptomically defined iNKT2 cells comprise precursors to iNKT1 and iNKT17•Most of thymic iNKT subsets seem to have the potential to egress the thymus•The transcription cofactor FHL2 controls specification of the iNKT1 effector fate
Baranek et al. perform an unbiased single-cell transcriptomic analysis of thymic iNKT cells, which reveals an unappreciated transcriptional and functional heterogeneity among these innate T cells. Mathematical modelling and biological approaches yield a model that may reconcile the current conflicting models.
G-protein-coupled receptors (GPCRs) are crucial cell surface receptors that transmit signals from a wide range of extracellular ligands. Indeed, 40% to 50% of all marketed drugs are thought to ...modulate GPCR activity, making them the major class of targets in the drug discovery process. Binding assays are widely used to identify high-affinity, selective, and potent GPCR drugs. In this field, the use of radiolabeled ligands has remained so far the gold-standard method. Here the authors report a less hazardous alternative for high-throughput screening (HTS) applications by the setup of a nonradioactive fluorescence-based technology named Tag-lite®. Selective binding of various fluorescent ligands, either peptidic or not, covering a large panel of GPCRs from different classes is illustrated, particularly for chemokine (CXCR4), opioid (δ, µ, and κ), and cholecystokinin (CCK1 and CCK2) receptors. Affinity constants of well-known pharmacological agents of numerous GPCRs are in line with values published in the literature. The authors clearly demonstrate that the Tag-lite binding assay format can be successfully and reproducibly applied by using different cellular materials such as transient or stable recombinant cells lines expressing SNAP-tagged GPCR. Such fluorescent-based binding assays can be performed with adherent cells or cells in suspension, in 96- or 384-well plates. Altogether, this new technology offers great advantages in terms of flexibility, rapidity, and user-friendliness; allows easy miniaturization; and makes it completely suitable for HTS applications.
•We confirm the efficacy of spa therapy in knee osteoarthritis (KOA) for pain and disability.•We show for the first time that spa therapy may help increase physical activity in patients with KOA, ...with limited effect of an additional self-management exercise program.•The benefits of a self-management education program were a significant alleviation of fears and beliefs about KOA and physicians (KOFBeQ) and anxiety (HAD) at 3 months after treatment.
The efficacy of spa therapy in osteoarthritis (OA) has ever been demonstrated, with a good level of evidence for pain and disability. The effect of a self-management program with spa therapy on physical activity (PA) level has never been demonstrated.
This study aimed to assess, at 3 months, the effectiveness of 5 sessions of a self-management exercise program in patients with knee OA (KOA) who benefit from 18 days of spa therapy and received an information booklet (on proposed physical exercises) on improvement in at least one PA level.
This was an interventional, multicentre, quasi-randomized controlled trial with a cluster randomized design (1-month period). People 50 to 75 years old with symptomatic knee OA were included in 3 spa therapy centres in France (Bourbon Lancy, Le Mont Dore, Royat). Both groups received conventional spa therapy sessions during 18 days and an information booklet on the benefits of PA practice for KOA. The intervention group additionally received 5 self-management exercise sessions. The main outcome was improvement in at least one PA level according to the International Physical Activity Questionnaire (IPAQ) short-form categorical score (low to moderate or high, or moderate to high) at 3 months. Secondary outcomes were the evolution of PA (MET-min/week), disability, pain, anxiety, depression, self-efficacy, fears and beliefs concerning KOA, barriers to and facilitators of regular PA practice, consumption of painkillers and adherence to physical exercise program at 3 months. Assessors but not participants or caregivers were blinded.
In total, 123 patients were randomized, 54 to the intervention group and 69 to the control group. Considering the main outcome, at 3 months, 37% of patients in the intervention group showed improvement in at least one PA level according to the IPAQ categorical score versus 30.4% in the control group (P=0.44). In the intervention group, 13 (24.1%) patients showed improvement from low to moderate PA level (vs. 8 11.6% in the control group), 2 (3.7%) from low to high (vs. 2 2.9%) and 5 (9.3%) from moderate to highvs. 11 15.9%). Both intervention and control groups showed increased IPAQ continuous scores (MET-min/week) at 3 months, although not significantly. HAD anxiety and depression scores were significantly reduced in the intervention group (P=0.001 and P=0.049, respectively) and the perception of PA was better in the intervention than control group for motivation and barriers scores (P=0.019 and P=0.002, respectively).
This study showed the lack of impact of a short self-management program on PA level in addition to 18-day spa therapy for KOA, but both intervention and control groups showed improved PA level.
PDF
