Journal of immunology最新文献

Highly immunodeficient BRGSF mice have proven to be suitable for reconstitution with human cord blood cell-derived CD34+ hematopoietic stem cells, enabling the generation of human immune system (HIS) mice. Here, we employ a robust comparative approach utilizing human lung biopsies to characterize the immunological landscape of the lung in BRGSF-HIS mice. Although only macrophages of mouse origin are detected in the alveoli, immunophenotyping of the lung interstitium reveals the presence of human natural killer cells and various T-cell subsets, including CD4+ and CD8+ T cells, γδ T cells, and regulatory T cells, at percentages comparable to those observed in human lungs. Monocytes and dendritic cells predominate within the human myeloid compartment, while neutrophils are underrepresented. Nevertheless, the injection of exogenous human granulocyte colony-stimulating factor promotes the egress of human CD15+ cells, primarily consisting of mature neutrophils. Interestingly, human T cells from BRGSF-HIS mice are responsive to CD3-mediated stimulation, and monocyte-derived macrophages exhibit remarkable in vitro plasticity in M1/M2-like polarization. In adherent myeloid cells from BRGSF-HIS mouse lungs, LPS challenges elicit the secretion of human cytokines, including IL-6, CCL17, IL-10, and IL-1RA, confirming the ability of human myeloid cells to mount inflammatory responses. These findings demonstrate that BRGSF-HIS mice possess human myeloid and lymphoid cell compartments in the lung interstitium comparable to humans. Although some limitations should be considered to ensure the suitability of HIS mice for specific research contexts, BRGSF-HIS mice provide valuable insights for studying immune mechanisms in certain human lung diseases.

Spring viremia of carp virus (SVCV) represents a significant threat to cyprinids, particularly common carp (Cyprinus carpio). The disease caused by this virus is characterized by tissue necrosis and petechial hemorrhages. However, the pathogenesis of SVCV infection remains poorly understood. Pyroptosis, a recently identified form of programmed cell death, plays a crucial role in host-pathogen interactions and provides a novel approach for studying inflammation-related diseases. This study demonstrates that SVCV induces gasdermin Eb-dependent pyroptosis through activation of NLRP3 and initiation of cellular inflammatory death. This process results in the production of active caspase-B (p20), mature interleukin-1β, and lactate dehydrogenase release. The gasdermin Eb-dependent pyroptosis induced by SVCV is inhibited by treatment with either an NLRP3 inhibitor or a caspase-B inhibitor. Mechanistic investigations reveal that the SVCV-G protein plays a critical role in inducing pyroptosis, while the host-interacting protein, voltage-dependent anion channel 2 (VDAC2), is essential for inflammasome activation by maintaining NLRP3 protein stability. In vivo experiments show that DIDS, a VDAC2 inhibitor, reduces SVCV-induced pyroptosis and NLRP3 inflammasome activation, thereby alleviating inflammation and tissue damage in zebrafish. Furthermore, zebrafish larvae with VDAC2 gene knockdown exhibit reduced cellular damage from SVCV infection, resulting in increased survival. These findings elucidate a mechanism by which SVCV activates the NLRP3 inflammasome, inducing inflammation and pyroptosis, and provide novel insights into the pathogenesis of SVCV infection.

Mucosal-associated invariant T (MAIT) cells play a vital role in immune responses, yet their involvement in autoimmune diseases such as Sjögren's disease (SjD) remains unclear. CD55, a key regulator of complement activation, influences immune cell function. This study investigates CD55 expression on MAIT cells in SjD patients and healthy controls, evaluating its potential as a diagnostic marker. Flow cytometry was used to assess CD55 expression on MAIT cell subsets, including CD4-CD8+, CD4+CD8-, double-positive (DP), and double-negative (DN), in peripheral blood from SjD patients and healthy controls. Functional markers (PD-1, CD83, and CD44), cytokine production (TNF-α, IFN-γ, IL-17, IL-22), and granzyme B (GZMB) secretion were analyzed following 5-OP-RU and brefeldin A stimulation. Receiver operating characteristic (ROC) analysis was conducted to evaluate the diagnostic utility of CD55 expression. CD55 was highly expressed on MAIT cells, with the highest expression intensity observed in DP MAIT cells, followed by CD4+CD8- MAIT and CD4-CD8+ MAIT, with the lowest expression found in DN MAIT cells. CD55hi MAIT cells demonstrated significantly higher percentages of PD-1+, CD83+, and CD44+ cells, along with enhanced cytokine and GZMB secretion following stimulation. In SjD patients, CD55 expression was significantly upregulated in MAIT cells. ROC analysis indicated that CD55hi MAIT cells have potential diagnostic value for SjD. CD55 is highly expressed on MAIT cells, with upregulation in SjD patients correlating with inflammation and autoantibodies, suggesting CD55hi MAIT cells as a potential diagnostic marker for SjD.

Although alternatively-activated macrophages (AAM) have been implicated in the resolution of inflammation and tissue repair, their exact role, heterogeneity and origin in vivo remain incompletely defined. Here we show that distinct subsets of macrophages can acquire alternatively activated phenotypes in response to tissue injury where these cellular subsets display contrasting spatiotemporal dynamics and differentially contribute to the resolution of inflammation and tissue repair. By studying a model of cardiotoxin-induced muscle injury, we identify a population of monocyte-derived AAM characterized by expression of arginase-1 (Arg-1) and triggering receptor expressed on myeloid cells 2 (Trem2) that emerged in response to injury and fostered clearance of dying neutrophils and necrotic myofibers as well as the subsequent resolution of inflammation. A second population of AAM, which were marked by robust expression of resistin-like molecule alpha (Relmα) and mannose receptor C-type 1 (CD206), displayed a predominantly resident character and clustered around capillaries where they coordinated the recruitment of eosinophils as well as the subsequent process of tissue repair. Our data thus indicate a substantial heterogeneity among AAM subsets and help to define their specialized functions and roles during inflammation and tissue repair.

Pulmonary infections often fail to produce long-lived immune memory and the underlying mechanism(s) for this are unclear. Given the complex interactions between cells within the lung, we predicted intrinsic and extrinsic factors contribute to development of poor memory immune responses. To identify these factors, we used a multiomics approach to determine host-driven responses that undermine or support development of effective immune responses in two mouse models of pulmonary bacterial infections. Single cell RNA analysis and spatial imaging of the lung revealed that, in contrast to Bordetella pertussis driven immunity, subpar responses following Francisella tularensis infection were associated with the inability of T cells to readily proliferate upon re-challenge and absence of formation of iBALT. Further, we also identified that these features were partially a consequence of IFN-γ driven reprogramming of endothelial cells resulting in expression of IDO1 and dysregulated tryptophan metabolism. Interestingly, IDO1 expression and imbalanced tryptophan persisted even after clearance of the primary infection. The importance of expression of IDO1 was confirmed using IDO1 knock out mice. Specifically, these animals could withstand higher doses of the initial infection and developed significantly larger pools of functional T cells compared to wild type controls. Together, these results demonstrate critical crosstalk among cells in the lung that influences spatial organization of immune cells which affects the ability to develop effective memory immune responses against secondary bacterial infection. Our data also underscores the challenge of utilizing a live vaccine strategy against tularemia and the necessity for identifying novel, acellular vaccine candidates.

Natural killer (NK) cells are specialized lymphocytes that help protect against viruses and cancer. However, in the context of bacterial infections, NK cells can be harmful, rather than protective. Such immune pathogenesis by NK cells has been linked to the overproduction of proinflammatory cytokines like interferon-gamma (IFN-γ). In this context, IFN-γ-deficient mice display increased survival rates in response to Staphylococcus aureus (S. aureus) infection. However, little is known about how NK cells respond to S. aureus in humans, which causes life-threatening, invasive systemic infections with high mortality rates. In this study, we found that the peripheral blood of patients with bloodstream S. aureus infection was enriched for CD57- NKG2A+ NK cells with greater cytokine-producing capacity, compared to healthy controls and those hospitalized with Escherichia coli bloodstream infections. As a possible mechanistic cause, superantigens from S. aureus promoted the expansion of CD57- NKG2A+ NK cells that produced IFN-γ through a mechanism that appears to be IL-12 independent and exhibited reduced levels of CD16 compared to unstimulated NK cells. These data suggest that S. aureus bloodstream infection in humans promotes a phenotypic shift toward CD57- NKG2A+ NK cells with greater IFN-γ-producing capacity, providing a plausible way to promote inflammation-driven disease pathogenesis.

Adjuvants are widely used to boost the immune response during vaccination protocols. Our group has previously reported that repeated intraperitoneal administration of alum in mice, known as adjuvant conditioning (AC), creates an immunosuppressive environment that delays allogeneic graft rejection through NLRP3-dependent MDSC expansion. However, little is known about the effects of AC on the reprogramming of peritoneal cavity cells, particularly the different peritoneal macrophage populations, and the impact on the adaptive immune response. We found a population-specific immune response to alum, with small peritoneal macrophages (SPMs) being more prone to inflammasome activation than large peritoneal macrophages (LPMs) in vitro. In vivo, alum exposure led to NLRP3-dependent macrophage disappearance reaction (MDR) of LPMs, which could be explained by aggregate formation and migration to the omentum. AC also induced the reprogramming of resident macrophages and infiltrating monocytes towards a less inflammatory state, making them more vulnerable to bacterial infections, but recruited neutrophils with enhanced killing ability. This suggests that AC may influence both innate and adaptive immunity in distinct ways, reprogramming cells to different profiles, and indicating its potential as an immunosuppressive treatment for autoimmune diseases and transplant rejection.

Foxp3+ regulatory T (Treg) cells with antigen receptors (TCRs) specific for host peptides suppress autoimmunity. Paradoxically, Treg cells are also found in CD4+ T-cell populations specific for foreign (nonhost) peptides. We investigated the origin and function of these Treg cells in mice. Populations of foreign peptide-specific naïve CD4+ T cells contained Foxp3- conventional (Tconv) and Foxp3+ Treg cells in about a 90:10 ratio. Both types of T cells proliferated in parallel after vaccination with the foreign peptide in incomplete or complete Fruend's adjuvants and formed memory cells. The Tconv population failed to express Foxp3, and formed Th1, Th17, and T follicular helper cells, whereas the Treg population largely retained Foxp3, and formed Th1- and Th17-like cells. The Treg cells specific for a foreign peptide had no effect on the proliferation of Tconv cells specific for that peptide but partially reduced Th1 cells in that population. Thus, foreign epitope-specific naïve Treg cells fine-tune the primary response of Tconv cells specific for the same epitope by curbing the Th1 fate while allowing a robust response.

Endosomal toll-like receptors TLR7 and TLR8 are critical sensors of microbial RNA that initiate antiviral and antibacterial immune responses through type I interferon (IFN) and proinflammatory cytokine production. While TIRAP is traditionally associated with plasma membrane TLR signaling, recent evidence suggests that it also contributes to signaling via endosomal TLRs. Here, we examined the role of TIRAP in TLR7/8 signaling using P7-Pen, a novel SLAMF1-derived peptide that disrupts the TIRAP-MyD88 interaction. In primary human monocytes and a whole blood model, P7-Pen inhibited TLR7- and TLR8-induced expression and secretion of IRF5-regulated cytokines IFNβ, IL-12p40, and IL-12p70, without effect on TNF or IL-6. Mechanistically, P7-Pen blocked TIRAP recruitment to the TLR8-MyD88 complex, leading to reduced late-stage IRAK1 activation, Akt and IKKα/β phosphorylation, and downstream IRF5 dimerization and nuclear translocation. Inhibition of Staphylococcus aureus-induced cytokine production by P7-Pen was associated with reduced bacterial phagocytosis, impairing endosomal delivery of bacterial RNA. Notably, P7-Pen failed to inhibit murine TLR7 responses, which correlated with a lack of TIRAP recruitment to MyD88 in mouse macrophages following TLR7 ligand stimulation, highlighting species-specific differences in TLR signaling mechanisms. These findings support a noncanonical role for TIRAP in regulating IRF5-dependent signaling downstream of human TLR7 and TLR8, and demonstrate that selective disruption of TIRAP recruitment by a SLAMF1-derived peptide effectively attenuates IFNβ production. This strategy may hold therapeutic potential in diseases characterized by dysregulated type I IFN responses, such as systemic lupus erythematosus and chronic infections.

NOD2 is primarily recognized as a cytosolic bacterial sensor of peptidoglycan, activating a downstream Rip2/NF-κB-mediated antimicrobial signaling pathway and playing a vital role in host defense against bacterial infections. NOD2 also appears to play a critical role in immune homeostasis, as NOD2 variants have been linked to multiple human inflammatory diseases, including common polymorphisms that increase the risk of Crohn's disease and rare mutations that cause Blau syndrome. The cellular mechanisms through which mutated NOD2 contributes to disease remain unclear and are currently under investigation. A T cell-intrinsic role for Nod2 in infection and inflammation was suggested almost 15 years ago, leading to intense scrutiny in this research area. This review highlights recent studies establishing a T cell-intrinsic role for NOD2 downstream of T-cell receptor and co-receptor signaling and delineates how NOD2 shapes T-cell responses in both homeostasis and disease, with implications for Blau syndrome and Crohn's disease.