Our cover features images related to flow cytometry techniques widely used for analysis of function and phenotypes of major human and murine immune cell subsets, superimposed on a multidimensional immune cell population scatter plot. These images are taken from the third edition of EJI's Flow Cytometry Guidelines by Cossarizza et al., a comprehensive resource prepared by flow cytometry and immunology research experts from around the world.
In pDCs, BTK-inhibition (BTKi) blocks the IFN-α production via TLR-9, but not via TLR-7. Upon TLR-7 stimulation, BTKi enhances the production of IFN-α by blocking the inhibitory BDCA-2 pathway. This might explain partially the failure of BTKi in SLE and is of interest for BTKi trials in multiple sclerosis.
Innate immune cells express a plethora of inhibitory receptors, many of which recognize molecular patterns. An appropriate balance between signaling via activating and inhibitory pattern recognition receptors is important for a proper immune response while preventing immunopathology. V-set and transmembrane domain containing 1 (VSTM1), also known as signal inhibitory receptor on leukocytes-1 (SIRL-1), is an inhibitory receptor expressed on myeloid cells. VSTM1 can modulate the function of myeloid cells, by inhibiting reactive oxygen species and neutrophil extracellular trap formation. VSTM1 recognizes shared molecular patterns both from endogenous and microbial origin, defining it as an inhibitory pattern recognition receptor. VSTM1 is involved in various pathological conditions, including autoimmune disorders and cancer, and its restricted expression on myeloid cells highlights its potential as a specific therapeutic target. This review summarizes the characteristics and function of VSTM1 in health and disease.
Thymocyte β-selection and positive-selection depend on TCR signaling via the immune adaptors SLP-76 and LAT. Gads bridges the recruitment of SLP-76 to LAT, yet is not required for the maturation of single positive (SP) thymocytes. To illuminate this paradox, we performed tamoxifen-induced ablation of Gads (GadsiKO), accompanied by the expression of tdTomato, and compared the development of Gads-expressing (Tom−) and Gads-ablated (Tom+) thymocytes within the same mouse. GadsiKO (Tom+) thymocytes exhibited impaired β- and positive-selection, yet δ-selection was not affected. While susceptible to apoptosis ex vivo, the marked accumulation of self-MHC nonresponding (CD5−) GadsiKO DP thymocytes suggested the possibility of impaired death by neglect in situ. Further supporting this notion, GadsiKO CD5lo DP thymocytes exhibited reduced apoptosis in situ and reduced CD8-induced apoptosis ex vivo. Most GadsiKO CD4 SP thymocytes were positively selected, yet a distinct population of unselected (CD5− TCRβneg/low CCR7lo CD24hi) CD4 SP thymocytes was seen only in the absence of Gads. This unselected population did not include Treg or TCRγδ subsets; rather, it encompassed CD44lo CD25+ cells, resembling pre-β-selection thymocytes. Our results suggest that Gads promotes passage through key TCR-driven developmental checkpoints while repressing the progression of unselected DN and DP thymocytes.
The development of efficient immunosuppressants may bring significant benefits to patients after organ/stem transplantation and those with allergies or autoimmune diseases. MEK inhibitors were originally developed as anticancer reagents, but recent reports have suggested that they may have the potential to be immunosuppressants. Trametinib is a first-in-class MEK inhibitor. Here, we examined the effects of trametinib on the immune system and revealed its mechanism. Trametinib suppressed both CD4 and CD8 T-cell proliferation and activated T cells, which expressed CD25 and TIM3, in a dose-dependent manner in vitro. Trametinib also suppressed T cell-related cytokine secretion in a dose-dependent manner. Notably, trametinib suppressed T cell proliferation through the induction of G1 arrest and apoptosis in stimulated T cells. In addition, trametinib induced regulatory T cells (Tregs). We confirmed that low concentrations of trametinib (1 and 10 nM) were not toxic toward splenic naïve T cells and normal mouse liver cells. In this study, we demonstrated whether trametinib suppressed CD4 and CD8 T cell proliferation by inducing G1 arrest and apoptosis along with suppression of cytokine secretion.
Recent advances in multi-omics and spatially resolved single-cell technologies have revolutionised our ability to profile millions of cellular states, offering unprecedented opportunities to understand the complex molecular landscapes of human tissues in both health and disease. These developments hold immense potential for precision medicine, particularly in the rational design of novel therapeutics for treating inflammatory and autoimmune diseases. However, the vast, high-dimensional data generated by these technologies present significant analytical challenges, such as distinguishing technical variation from biological variation or defining relevant questions that leverage the added spatial dimension to improve our understanding of tissue organisation. Generative artificial intelligence (AI), specifically variational autoencoder- or transformer-based latent variable models, provides a powerful and flexible approach to addressing these challenges. These models make inferences about a cell's intrinsic state by effectively identifying complex patterns, reducing data dimensionality and modelling the biological variability in single-cell datasets. This review explores the current landscape of single-cell and spatial multi-omics technologies, the application of generative AI in data analysis and modelling and their transformative impact on our understanding of autoimmune diseases. By combining spatial and single-cell data with advanced AI methodologies, we highlight novel insights into the pathogenesis of autoimmune disorders and outline future directions for leveraging these technologies to achieve the goal of AI-powered personalised medicine.
Non-lymphoid tissue Tregs (NLT-Tregs) are critical for tissue homeostasis, inflammation control, and induction of tissue repair. Recent single-cell RNA sequencing data identified the expression of CD83 as part of an NLT-Treg signature, which is an essential molecule for the stability and differentiation of lymphoid Tregs. However, the biological significance of CD83 expression for NLT Tregs has not yet been elucidated. The present study explores for the first time the role of CD83 expression by lung-resident Tregs in the steady state and during asthma to understand its importance in barrier tissues. We evaluated the effect of Treg-specific CD83 deletion (CD83cKO) on the lung-resident T-cell compartment and cytokine profile. CD83-deficient lung Tregs are less differentiated but more activated, resulting in unrestrained T-cell activation. Further, CD83cKO mice were challenged in an asthma model and showed an accelerated disease progression, driven by Th2-biased T-cell responses. CD83cKO Tregs exhibited enhanced responsiveness to IL-4, leading to insufficient control of Th2-differentiation from naïve T cells. These findings underscore the pivotal role of CD83 in the NLT-Treg-mediated modulation of Th2 responses. Overall, our results highlight CD83 as a key player in tissue homeostasis and inflammatory responses, suggesting potential therapeutic implications for inflammatory disorders such as asthma.
Regulatory T cells (Tregs) are a subset of T cells defined by the expression of Forkhead box protein P3 (FoxP3) playing a crucial role in regulating effector T cell activity. Tregs accumulate in the tumor microenvironment facilitating tumor growth. Thus, targeting FoxP3+ Tregs could improve cancer immunotherapies. Here, we conducted a high-throughput, phenotypic screening of a drug repurposing library to identify compounds downregulating FoxP3 expression in human primary T cells. We identified the tyrosine kinase inhibitor bosutinib and the STAT3 inhibitor nifuroxazide effectively downregulating FoxP3 expression. To identify more potent compounds, structural analogs of these two compounds were searched and validated. These analogs were found to reduce FoxP3 expression in a similar- or more potent manner than the original hits. All compounds inhibited Treg suppressive functions and reduced the expression of Treg activation markers. Importantly, bosutinib disrupted FAK and CaMKII signaling more potently in Tregs, whilst nifuroxazide and its analog NA16 targeted STAT3 protein levels more effectively in Tregs. Additionally, bosutinib and NA16 targeted effector Tregs more effectively than other Treg subsets. In summary, bosutinib, nifuroxazide, and their analogs inhibited FoxP3 expression, Treg suppressive abilities, and Treg activation effectively, which could serve as tools for the improvement of current cancer immunotherapies.
NADPH-oxidase (NOX)-derived reactive oxygen species (ROS) have been described to play essential roles in B-cell activation processes. However, several key questions concerning NOX activity and subsequent ROS production remain unaddressed, including fundamental processes such as differentiation, functional competence, cellular metabolism, and viability. This study investigated these questions in a murine B-cell response after secondary immunization. We combined single-cell transcriptomics and single-cell detection of NOX activity and observed that various subsets of B cells dynamically express NOX1 and NOX2. The NOX+ cellular phenotype correlated with increased activity of metabolic pathways, augmented lactate production, lower IgG secretion rates, and markers for longevity. The NOX+ cellular phenotype was also associated with increased cellular stress and apoptosis, underscoring the intricate relationship between ROS and cellular survival. Consequently, these insights advance our understanding of how long-lived humoral immunity is formed.
The inflammatory response triggered by Toll-like receptors (TLRs) may implicated in the development of the pathogenesis of adult-onset Still's disease (AOSD). This study evaluated the efficacy of TLR inhibitor peptides, specifically TLR inhibitor peptide 1 (TIP-1) and MAL/MyD88 inhibitory peptide 2 (MIP-2) in animal models of AOSD. THP-1 cells were stimulated with TLR agonists and treated with TIP-1 or MIP-2. Interferon (IFN)-γ knock-out mice were induced with AOSD-like symptoms using Mycobacterium mixed with Freund's complete adjuvant (CFA), then treated with the peptides. THP-1 cells treated with TIP-1 and MIP-2 showed significantly decreased expression of TLRs agonist-induced MyD88 and phosphorylated NF-κB, except TLR9 agonists. Furthermore, the peptides resulted in a significant decrease in the concentrations of interleukin (IL)-1β and IL-6 in the culture supernatants, except TLR9 agonists. In animal models of AOSD, treatment with inhibitor peptides significantly improved their clinical symptoms. The administration of these peptides resulted in a significant decrease in serum levels of IL-1β and IL-18. The expression of inflammatory cytokines were downregulated in the spleen and lymph node of TIP-1 and MIP-2 treated mice. These findings suggest that TIP-1 and MIP-2 may be effective candidates for AOSD treatment, as they have broad specificity for TLRs.
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