Browse Articles

Adjuvants orchestrate cross-organ induction of mucosal CD8+ T cell immune responses in respiratory tracts

Abstract Mucosal immunity is paramount for combating respiratory infections, but conventional vaccination methods, such as intramuscular injection, often struggle to induce it. Although direct mucosal vaccination is effective, it carries an increased risk of respiratory adverse effects, making it particularly challenging for individuals with chronic respiratory diseases. Consequently, developing a strategy to induce sufficient mucosal immune responses without modifying conventional vaccination methods would be highly desirable. The potential of vaccine adjuvants to facilitate such cross-organ induction of mucosal immunity, given their established role in enhancing and shaping immune responses, is currently not well understood. In this study, we investigated the effects of intramuscular vaccination using OVA or RBD-Fc formulated with four distinct adjuvants, aluminum hydroxide, squalene-based emulsion (AddaVax), STING agonist diamidobenzimidazole (diABZI), and immunostimulatory complexes (ISCOMs). All of these adjuvants increased serum antigen-specific IgG titers and correspondingly elevated IgG levels in bronchoalveolar lavage fluid (BALF), but their impact on mucosal IgA was limited. Interestingly, only ISCOMs significantly increased the proportion of pulmonary antigen-specific CD8+ T cells, a significant amount of which were in a tissue-resident memory phenotype. Subsequent mechanistic investigations showed that ISCOMs-activated dendritic cells promoted the expression of α4β1 integrin on CD8+ T cells, a key factor believed to mediate T cell residency in the lungs. Our findings indicate that judicious adjuvant selection can facilitate the induction of mucosal immune responses via intramuscular vaccination, a well-accepted and safer route.

Inflammatory genital strain of <i>Chlamydia trachomatis</i> elicits a Th17 immune response

Abstract In humans, infection with Chlamydia trachomatis can result in chronic infection with severe reproductive consequences. The immune response elicited by natural infection fails to protect against reinfection and can contribute to tissue inflammation and damage. CD4+ T cells are key mediators of protection against C. trachomatis. However, these same cells, together with neutrophils, also contribute to tissue pathology. The identity and effector functions of the CD4+ T cells that contribute to protection, pathology, or both remain poorly defined. Notably, C. trachomatis pathology is serovar specific. Infection with serovar D induces severe tissue inflammation in the female upper genital tract, whereas infection with serovar L2 does not. Using a murine model of genital infection, we found that infection with serovar D selectively drives the polarization of naïve CD4+ T cells into inflammatory Th17 cells through the induction of Th17-polarizing cytokines, such as IL-1β, IL-6, and IL-23, compared with serovar L2 infection. Single-cell RNA sequencing of CD4+ T cells from the uteri of serovar D–infected mice revealed a Th17-skewed response with transcriptional features of an inflammatory phenotype, including upregulation of Bhlhe40 and Il1r1. Th17 cells have been reported to contribute to pathology through secretion of pro-inflammatory cytokines that recruit neutrophils and promote tissue damage. Together, these findings demonstrate that serovar D promotes pro-inflammatory CD4+ T-cell responses that could contribute to immunopathology in C. trachomatis infection, in contrast to the response elicited by serovar L2. They also underscore the importance of developing a vaccine that elicits protective immunity while minimizing harmful inflammatory responses.

Epigenetic control of p53 activity in regulatory T cells maintains their identity to prevent inflammation

Abstract Regulatory T cells (Tregs) are critical guardians of immune homeostasis that must operate in diverse and often inflammatory conditions. However, the mechanisms that Tregs use to maintain their stability and function, especially in response to the stresses of distinct microenvironments, remain incompletely understood. Previous work identified the repressive chromatin modification histone 3 lysine 27 trimethylation (H3K27me3) as a rheostat for Treg function. Here, we find that loss of H3K27me3 in Tregs activates the tumor suppressor p53. Stabilization of p53 using the MDM2 inhibitor Nutlin-3 protected Tregs from losing their master transcription factor FOXP3 in vitro when cultured with the T helper 17 cytokines interleukin-6 and interleukin-1β, while p53 deficiency rendered Tregs more prone to FOXP3 loss. Treg-specific p53 deficiency resulted in the accumulation of cells that had lost Foxp3 expression (“ex-Tregs”) and a reduction of suppressive markers on Tregs specifically in the colon. Additionally, these mice exhibited inflammation in the colon at homeostasis and increased severity of induced colitis. These results demonstrate a specific role for p53 in the maintenance of Treg stability in inflammatory T helper 17–polarizing environments and present a possible target for improving Treg-based immunotherapies for diseases defined by intestinal inflammation, such as inflammatory bowel disease.

Genetic deletion of the inflammatory bowel disease-associated risk gene Rgs14 aggravates experimental colitis

Abstract Regulators of G protein signaling (RGS) deactivate G proteins associated with G protein-coupled receptors (GPCRs), a large receptor family with diverse functions. Of the 20 RGS, the Rgs14 single-nucleotide polymorphism is associated with inflammatory bowel disease, and Rgs14 expression is higher in macrophages than in epithelial cells. This manuscript describes a novel conditional mouse line that enables deletion of Rgs14 in macrophages and intestinal epithelial cells. We demonstrate that Rgs14 deletion in macrophages increases their reactive oxygen species production and their ability to induce T cell proliferation. The deletion in macrophages, but not in epithelial cells, exacerbates colitis severity. This novel conditional mouse model will facilitate further investigation of Rgs14 in inflammatory bowel disease and potentially in other areas, including metabolism, neuroscience, and aging.

IFITM1 differentially regulates antibacterial immunity and immunopathology but is dispensable for antiparasitic responses

Abstract Interferon-induced transmembrane (IFITM) proteins underpin antiviral responses, yet their role in bacterial infections remains underexplored, particularly for parasites. We probed the role of IFITM1 in Mycobacterium tuberculosis (Mtb), Listeria monocytogenes (Lm), and Leishmania major infection using IFITM1 knockout mice. Notably, IFITM1 was upregulated in murine and human macrophages, as well as in PBMCs during active tuberculosis (TB), subsiding with therapy. IFITM1 also accumulated in the lungs of outbred mice and macaques that progressed to TB. IFITM1-deficient mice displayed no differences in the acute phase; however, chronic Mtb infection revealed lower bacterial loads, mitigated lung pathology, dampened inflammatory cell recruitment, and decreased cytokines. IFITM1−/− macrophages curbed intracellular H37RV and HN878 growth, skewing proinflammatory cytokine (IL-1α, IL-1β, IL-6, and nitric oxide) production while phagosome maturation and autophagy remained unaffected. Furthermore, HN878-infected IFITM1−/− mice exhibited increased lung cell death by TUNEL staining, driving enhanced mortality. Lm similarly increased IFITM1 expression in macrophages, liver, and spleen. IFITM1−/− mice exhibited reduced early tissue burdens and serum IFN-γ, TNF, and IL-6, yet liver pathology escalated, driving mortality and suggesting dysregulated inflammation. These macrophages also limited intracellular Lm growth, with increased necrosis. By contrast, L. major footpad swelling and parasitic loads remained unaffected in knockout animals. Together, IFITM1 exacerbates TB and listeriosis pathology by calibrating inflammation against bacterial control, but plays no role in cutaneous leishmaniasis. These findings reveal IFITM1-specific contributions to bacterial but not parasitic infections, favoring disease tolerance.

Correction to: ABIN2 Function Is Required To Suppress DSS-Induced Colitis by a Tpl2-Independent Mechanism

ER stress amplifies inflammation via a dual mechanism involving IκBζ–XBP1s synergism and Regnase-1 degradation

Abstract Inflammatory diseases arise from complex interactions between immune signaling and cellular stress. Although endoplasmic reticulum (ER) stress is a key modulator of immunity, the mechanisms by which it promotes inflammatory pathology remain incompletely understood. Notably, ER stress–induced NF-κB activation alone is insufficient to account for robust IL-6 production, thus suggesting the involvement of additional regulators. Using bone marrow–derived macrophages and sepsis model mice, we identified the inducible transcription factor IκBζ as a critical mediator of this response, with ER stress synergizing with TLR signaling to markedly upregulate IκBζ. Mechanistically, ER stress triggered calcium-dependent signaling that led to IκB kinase–mediated degradation of the RNase Regnase-1, likely stabilizing Nfkbiz mRNA and promoting the accumulation of IκBζ, which was found to cooperate with the ER stress factor XBP1s to drive transcription of selected secondary-response genes, particularly Il6 and Nos2. Importantly, this synergy was required for excessive IL-6 production in septic mice, highlighting a gene-specific amplification pathway. Together, these findings identify a dual mechanism in which transcriptional synergy between IκBζ and XBP1s is coupled to posttranscriptional mRNA stabilization via Regnase-1 degradation, thereby linking proteotoxic stress to hyperinflammatory responses. Our results establish ER stress–mediated IκBζ accumulation as a key driver of inflammatory pathogenesis and a potential therapeutic target in ER stress–associated inflammatory disorders.

Correction to: STING agonists drive recruitment and intrinsic type I interferon responses in monocytic lineage cells for optimal anti-tumor immunity

CSF1R-dependent macrophages control B cell development and function in the chicken immune system

Abstract Acquired immunity in mammals depends upon capture and presentation of antigens by specialized macrophage populations in splenic marginal zone and lymph node sinuses and follicular dendritic cells within germinal centers. Cells referred to as follicular dendritic cells in chickens express CSF1R, the receptor for CSF1 and IL34. We used single-cell RNA sequencing on CSF1R+ cells from chicken spleen to identify monocytes and 2 distinct populations of macrophages. TIMD4/C1Q/MAFB+ macrophages were enriched for expression of genes involved in iron metabolism and antigen capture and presentation, suggesting a functional relationship with both red pulp and marginal zone macrophages in mammals. Conversely, a MARCO/VSIG4+ population expressed SPIC, a transcription factor associated with red pulp macrophages in mammals, but also expressed receptors and trophic factors associated with mammalian follicular dendritic cells. SPIC+ cells were located within follicles in spleen, cecal tonsil, and bursa. We conclude that a specialized population of CSF1R+, SPIC+ macrophages in birds differentiates to perform the function of follicular dendritic cells. To determine the function of CSF1R+ macrophages, we generated a CSF1R knockout in the chicken germ line. Mutant birds lack macrophages in the embryo. They were indistinguishable from wild type at hatch and behaved and fed normally; from days 5 to 6 after hatch, however, they failed to thrive. Loss of CSF1R function in hatchlings led to monocytopenia, granulocytosis, and loss of macrophage subpopulations in lymphoid organs. The loss of follicular macrophages in the bursa was associated with involution and severe B cell deficiency in the circulation and spleen.

Getting on your last nerve: IFNs and resistance to infection

Abstract Interferons (IFNs) affect almost all nucleated cells and induce transcriptional events that are associated with control of intracellular infections as well as regulatory pathways that influence inflammatory processes. How different hematopoietic and non-hematopoietic cell types interpret these signals is a reflection of cellular context and function. For example, neurons are often viewed as immunologically inert and have muted responses to IFNs. However, because neurons can be targeted by several classes of pathogens, there is a need for these cells to sense infection and respond to IFNs to engage anti-microbial activities. This review discusses the unique features of neuronal IFN signaling, emphasizing how JAK-STAT pathway engagement and downstream induction of interferon-stimulated genes (ISGs) shape intrinsic and extrinsic neuronal anti-pathogen defense.

The scaffolding protein AKAP79/150 shapes innate immune responses to allergen

Abstract Inhalation of house dust mite-derived allergens is a major factor leading to the development of asthma both in children and adults. Allergens stimulate Ca2+-dependent pro-inflammatory cytokine and chemokine gene expression through the opening of ORAI1 Ca2+ channels in the surface membrane of various immune cell-types within the lung. ORAI1 participates in a signalosome with the scaffolding protein A-kinase anchoring protein (AKAP)79/150 (encoded by the Akap5 gene), which binds numerous protein kinases, calcineurin and transcription factors required for cytokine expression. However, the role of AKAP79/150 in immune cell activation and the development of airway inflammation in response to allergens has not been established. We found that AKAP79/150 is expressed in mast cells and macrophages, where it has a pivotal role in driving pro-inflammatory cytokine production in response to house dust mite challenge. By contrast, AKAP79/150 expression in T cells was low and had little impact on cytokine release following T cell activation. Akap5−/− mice exhibited significantly reduced type 2 inflammation in the lungs following HDM exposure compared with wild-type controls. Our data demonstrate that AKAP79/150 is an important co-ordinator of inflammation within the lung in response to airborne allergens, through actions primarily on cells of the innate immune system.

Optineurin restrains IL-17–associated neuroinflammation in trigeminal ganglia to preserve sensory function after ocular HSV-1 infection

Abstract Neurotrophic keratitis (NK) arises when trigeminal sensory dysfunction reduces corneal sensation and compromises epithelial maintenance. Herpes simplex virus type 1 (HSV-1) establishes latency in the trigeminal ganglion (TG) and is a common trigger of acquired NK, yet the host programs that determine whether inflamed ganglia recover or degenerate remain poorly defined. Moreover, experimental models that faithfully capture NK-like neuroimmune pathology are limited. Using a murine ocular HSV-1 infection model, we identify optineurin (OPTN) as a key regulator of trigeminal nerve preservation. Optn−/− mice developed severe corneal opacity and rapid, persistent loss of corneal and whisker sensitivity despite comparable corneal viral titers. Droplet-based single-cell RNA sequencing of TGs at 30 days postinfection revealed reduced recovery of peripheral neuronal transcriptomes and coordinated enrichment of chemokine/NF-κB and Th17/IL-17 gene signatures across neurons, endothelial cells, and myeloid/lymphoid populations. Consistent with these transcriptional programs, IL-17 was elevated in Optn−/− TGs at 30 days, whereas the cornea and draining lymph nodes did not exhibit increased IL-17 production early after infection. Neuronal staining demonstrated loss of the synaptic marker SNCG without increased neuronal death, implicating IL-17–associated inflammation in neuronal dysfunction rather than acute ablation. Together, these findings identify OPTN as a neuroimmune checkpoint that restrains chronic IL-17–linked ganglionic inflammation to preserve sensory function and suggest that OPTN deficiency provides a tractable experimental model for studying HSV-associated NK.

Stabilization of highly expansive clay using synergistic EAF slag and water treatment sludge: a mechanical performance study

Reply: “Toward a more translational SS-ILD model: Sex differences, endpoints, and B cell targets”

SwiftMSeg: lightweight multi-scale local–global context modeling with transformer for medical image segmentation

Abstract Accurate medical image segmentation requires both fine boundary localization and robust contextual understanding, which is often difficult to achieve simultaneously, particularly in lightweight architectures. In this paper, we propose SwiftMSeg, a lightweight encoder–decoder framework that integrates a convolutional encoder, a transformer-based local–global–local module, and a hierarchical multi-scale decoder. The proposed framework addresses the boundary–context challenge by effectively combining progressive multi-scale refinement for fine boundary separation with global context modeling through long-range dependency aggregation. Extensive evaluations on publicly available colonoscopy, pathology, ultrasound, and magnetic resonance imaging datasets demonstrated the capability of SwiftMSeg to accurately segment diverse anatomical structures, ranging from tiny nuclei to polyps and large tumor regions. The model further demonstrated moderate domain-independent generalization on an external dataset, achieving Dice scores of 0.896 (colonoscopy), 0.860 (pathology), 0.850 (ultrasound), and 0.870 (MRI), consistently outperforming most baseline methods. In addition, it achieved improved boundary localization with lower Hausdorff distance (e.g., 16.43 in MRI and 33.89 in ultrasound) and reduced average symmetric surface distance, indicating more precise and stable segmentation. Statistical analysis further confirmed that the improvements of SwiftMSeg are significant ( $$p &lt; 0.001$$ ) with large effect sizes across modalities, validated by both paired t -tests and Wilcoxon tests. Despite its strong performance, SwiftMSeg remains highly efficient, requiring only 4.48M parameters and 0.940 giga floating-point operations per second (GFLOPs), reducing computational cost by approximately $$\sim$$ 53 $$\times$$ compared to the U-Net-based baselines (standard U-Net $$\sim$$ 31M parameters and $$\sim$$ 50 GFLOPs), while maintaining high segmentation accuracy. These results highlight the effectiveness of SwiftMSeg as a practical and scalable solution for real-world medical image segmentation across diverse modalities.

Inhba is transcriptionally regulated by Foxa1 through the PI3K/AKT signal pathway in acute lung injury

Abstract Acute lung injury (ALI) is a fulminant respiratory failure syndrome with no targeted therapy. We show that Inhba is sharply upregulated in the damaged lung tissue of mice and in BEAS-2B cells, and its abundance tracks with cytokine storm and reactive oxygen species (ROS). Mechanistically, AKT activation is associated with increased FOXA1 phosphorylation and abundance, which transcriptionally induce INHBA; this upregulation of INHBA is a key upstream driver of enhanced ROS production and cytokine release in experimental ALI. Genetic deletion or pharmacologic blockade of PI3K/AKT simultaneously lowered Foxa1 and Inhba, reduced TNF-α, IL-6, and ROS, and improved histologic injury scores and oxygenation. These findings establish the PI3K/AKT–Foxa1–Inhba axis as a central driver in experimental ALI models and support its potential as a druggable target for future investigation. Further validation in human ALI samples will be required to support clinical translation.

Optical vortex transfer and dispersion-controlled light propagation in an Er³⁺: YAG three-level quantum system

Complement C3 deficiency increases the effector and cytotoxic functions of NK cells and suppresses tumor growth

Abstract The complement system and natural killer (NK) cells play crucial roles in tumor growth and metastasis. The role of the complement system in affecting the phenotype and anti-tumor function of NK cells remains poorly understood. Using the B16F10 mouse melanoma model, we demonstrated that NK cells from C3−/− mice exhibit increased expression of activation receptors (NKG2D, NKp46, and Ly49H) and reduced inhibitory receptors (NKG2A, Ly49A, and KLRG1) and high cytotoxic activity compared to C3+/+ mice NK cells. C3−/− mice show reduced melanoma tumor growth and metastasis in an NK cell-dependent manner compared to C3+/+ mice. Intratumoral NK cells in C3−/− mice formed a unique phenotypic cluster characterized by higher expression of T-bet, CD69, GITR, CD62L, CCR7, and increased secretion of effector cytokines (IFN-γ, TNF-α, and GM-CSF) and granzyme B expression compared to C3+/+ mice. In C3−/− mice, NK cells from both the spleen and tumors exhibit markedly higher expression levels of C3aR and C5aR1 compared to those from wild-type mice. Activation of C3aR by C3a, leads to phosphorylation of AKT and STAT3 molecules, resulting in phenotypic changes to NK cells. Furthermore, antagonising complement anaphylatoxin receptors C3aR or C5aR1 in wild-type mice resulted in reduced tumor growth, accompanied by an increase in intratumoral effector NK cells. Together, we demonstrated that complement C3 regulates the effector and cytotoxic functions of NK cells, suggesting that targeting complement C3 and the anaphylatoxin receptor may be beneficial in controlling tumor growth in the clinic.

A staged vision-force collaborative framework for precision robotic insertion of metallic valve components

Single-cell profiling of immune activation, dysregulation, and reconstitution in rhesus macaques after measles virus infection

Abstract Protective immunity is induced by both, wild-type measles virus (WT MeV) and live-attenuated (LA) measles virus vaccine (LAMV), affording the opportunity to compare common and selective immunological underpinnings of immune protection. Here, peripheral blood mononuclear cells (PBMCs) were collected from rhesus macaques at several timepoints after infection with either virus for single-cell RNA/VDJ sequence analysis. Data revealed acute immune activation at 10/11 days post infection (dpi) with WT MeV, with increased frequencies of CD8 T cells, monocytes and NK cells, and B and T cell expansion and activation, most notably IgA+ B cells and cytotoxic CD8 T cells. Two interferon-stimulated genes (ISGs), IFI6 and IFI27, were upregulated selectively across PBMCs, with strongest ISGylation and JAK-STAT activation in monocytes. Furthermore, WT MeV-infected PBMCs were enriched among IgA+ B cells and Th17 CD4 T cells, expressing the highest levels of ISGs. However, lymphocyte depletion, with absolute or relative reduction in B, CD4, and CD8 T cells, preferential ISG expression in activated/memory but not naive B and T cells, as well as dampened acute NK cell activation suggested acute immune suppression. Subsequent immune reconstitution was implicated by increased frequencies of IgM+ memory B cell subtypes with lower IGHV somatic hypermutation (SHM) rates at 42/43/56 dpi. LAMV elicited distinct humoral and cellular responses, with greater induction of IgG+ than IgA+ B cells and differential cytotoxic CD8 T cells encoding distinct TRBV/TRAV genes, compared to WT MeV. LAMV infection induced no signs of immune suppression. Together, these data provide insights into distinct features of WT MeV and LAMV-induced immunity.