Abstract
The co-stimulatory and co-inhibitory immunoreceptors, DNAX accessory molecule-1 (DNAM-1) and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif ...(ITIM) domain (TIGIT), are paired activating and inhibitory receptors on T cells and natural killer (NK) cells. They share the ligands poliovirus receptor (PVR, CD155) and its family member nectin-2 (CD112), which are highly expressed on antigen-presenting cells (APCs), tumors and virus-infected cells. Upon ligation with the ligands, DNAM-1 and TIGIT show reciprocal functions; whereas DNAM-1 promotes activation, proliferation, cytokine production and cytotoxic activity in effector lymphocytes, including CD4+ T-helper cells, CD8+ cytotoxic T lymphocytes and NK cells, TIGIT inhibits these DNAM-1 functions. On the other hand, DNAM-1 competes with TIGIT on regulatory T (Treg) cells in binding to CD155 and therefore regulates TIGIT signaling to down-regulate Treg cell function. Thus, whereas DNAM-1 enhances anti-tumor immunity and inflammatory responses by augmenting effector lymphocyte function and suppressing Treg cell function, TIGIT reciprocally suppresses these immune responses by suppressing effector lymphocyte function and augmenting Treg cell function. Thus, blockade of DNAM-1 and TIGIT function would be potential therapeutic approaches for patients with inflammatory diseases and those with cancers and virus infection, respectively.
Type 1 innate lymphoid cells (ILC1s) regulate inflammation in the tissues; however, their role in anti-viral immunity remains largely unknown. In this issue of Immunity, Shannon et al. report that ...ILC1s invoke an anti-viral effect by producing interferon (IFN)γ at homeostasis, thereby limiting viral replication in the oral mucosa.
Type 1 innate lymphoid cells (ILC1s) regulate inflammation in the tissues; however, their role in anti-viral immunity remains largely unknown. In this issue of Immunity, Shannon et al. report that ILC1s invoke an anti-viral effect by producing interferon (IFN)-γ at homeostasis, thereby limiting viral replication in the oral mucosa.
Isolation of splenic macrophage subpopulations using an enzyme cocktail
Abstract
Tissue-resident macrophages in the spleen, including red pulp and white pulp macrophages, marginal zone macrophages ...(MZMs) and marginal zone metallophilic macrophages (MMMs), are highly heterogeneous as a consequence of adaptation to tissue-specific environments. Each macrophage sub-population in the spleen is usually identified based on the localization, morphology and membrane antigen expression by immunohistochemistry. However, their phenotypical and functional characteristics remain incompletely understood due to the difficulty of identification and isolation by flow cytometry. We used a cocktail of three enzymes (Collagenase D, Dispase I and DNase I), rather than traditional mechanical grinding, for isolation of each sub-population, which resulted in significant improvement of isolation of these macrophage sub-populations, particularly MZMs and MMMs, as determined by CD11bhiF4/80medTim4hi and CD11bhiF4/80medTim4med, respectively. This method should be helpful for molecular and functional characterization of each splenic resident macrophage sub-population.
Germinal centers (GCs) in secondary lymphoid organs generate large numbers of apoptotic B cells that must be eliminated by phagocytes to prevent the development of autoimmune diseases. Although ...tingible body macrophages engulf apoptotic GC B cells, whether stromal cells are also involved in this process is unclear. In this study, we identified marginal reticular cells (MRCs) as novel nonprofessional phagocytes for the clearance of apoptotic GC B cells in the spleen. We used CD19
(CD19
Z/EG) mice, which express enhanced GFP (eGFP) under the control of CD19
expression, to track B cells in the GCs after immunization with NP-chicken γ globulin plus aluminum salt. We demonstrated that the MRC population, as determined by expression of podoplanin or
, specifically showed an eGFP signal in the cytoplasm after immunization. These results suggest that MRCs contribute to the clearance of apoptotic B cells in GCs.
Although imbalances in gut microbiota composition, or “dysbiosis,” are associated with many diseases, the effects of gut dysbiosis on host systemic physiology are less well characterized. We report ...that gut dysbiosis induced by antibiotic (Abx) treatment promotes allergic airway inflammation by shifting macrophage polarization in the lung toward the alternatively activated M2 phenotype. Adoptive transfer of alveolar macrophages derived from Abx-treated mice was sufficient to increase allergic airway inflammation. Abx treatment resulted in the overgrowth of a commensal fungal Candida species in the gut and increased plasma concentrations of prostaglandin E2 (PGE2), which induced M2 macrophage polarization in the lung. Suppression of PGE2 synthesis by the cyclooxygenase inhibitors aspirin and celecoxib suppressed M2 macrophage polarization and decreased allergic airway inflammatory cell infiltration in Abx-treated mice. Thus, Abx treatment can cause overgrowth of particular fungal species in the gut and promote M2 macrophage activation at distant sites to influence systemic responses including allergic inflammation.
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•Antibiotic treatment induced gut fungal overgrowth•Gut fungal overgrowth promoted allergic airway inflammation•Gut fungal overgrowth elevated plasma PGE2 that promoted M2 macrophage polarization•M2 macrophage was involved in allergic airway inflammation
Antibiotic treatment induces dysbiosis. The effects of dysbiosis on host physiology are just emerging. Kim et al. find that antibiotic treatment of mice facilitates overgrowth of a gut commensal Candida species, which increases plasma concentration of prostaglandin E2. Fungi-induced prostaglandin E2 in turn promotes M2 macrophage activation and thus exacerbates allergic airway inflammation.
Innate lymphoid cells (ILCs) are tissue-resident innate lymphocytes that have functions to protect the hosts against pathogens and that regulate tissue inflammation and homeostasis. ILC subsets ...rapidly produce particular cytokines in response to infection, inflammation, and tissue injury at the local environment. Type 1 ILCs (ILC1s) promptly and abundantly produce interferon (IFN)-γ but lack appreciable cytotoxic activity. ILC1s share many phenotypic, developmental, and functional characteristics with natural killer (NK) cells, which are circulating innate lymphocytes with potent natural cytotoxicity. However, recent studies have established ILC1s as distinct from NK cells. ILC1s predominantly reside in the liver—they initially were discovered as a liver-resident ILC subset—as well as in other lymphoid and non-lymphoid tissues. Accumulating evidence has demonstrated that ILC1s play an important and unique role in host protection and in immunomodulation in their resident organs. However, the pathophysiological role of tissue-resident ILC1s remains largely unclear. In this review, we summarize emerging evidence showing that ILC1s not only contribute to inflammation to protect against pathogens but also promote tissue protection and metabolism. We highlight a unique function of ILC1s in their resident tissues.
The programmed cell death‐1/programmed cell death‐ligand 1 (PD‐1/PD‐L1) pathway is involved in preventing immune system‐mediated destruction of malignant tumors including glioblastoma. However, the ...therapeutic influence of PD‐1/PD‐L1 inhibition alone in glioblastoma is limited. To develop effective combination therapy involving PD‐1/PD‐L1 inhibition, we used a non‐replicating virus‐derived vector, hemagglutinating virus of Japan‐envelope (HVJ‐E), to inhibit tumor cell PD‐L1 expression by delivering siRNA targeting PD‐L1. HVJ‐E is a promising vector for efficient delivery of enclosed substances to the target cells. Moreover, HVJ‐E provokes robust antitumoral immunity by activating natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), and by suppressing regulatory T lymphocytes (Treg). We hypothesized that we could efficiently deliver PD‐L1‐inhibiting siRNAs to tumor cells using HVJ‐E, and that synergistic activation of antitumoral immunity would occur due to the immunostimulating effects of HVJ‐E and PD‐1/PD‐L1 inhibition. We used artificially induced murine glioma stem‐like cells, TS, to create mouse (C57BL/6N) glioblastoma models. Intratumoral injection of HVJ‐E containing siRNA targeting PD‐L1 (siPDL1/HVJ‐E) suppressed the expression of tumor cell PD‐L1 and significantly suppressed tumor growth in subcutaneous models and prolonged overall survival in brain tumor models. Flow cytometric analyses of brain tumor models showed that the proportions of brain‐infiltrating CTL and NK cells were significantly increased after giving siPDL1/HVJ‐E; in contrast, the rate of Treg/CD4+ cells was significantly decreased in HVJ‐E‐treated tumors. CD8 depletion abrogated the therapeutic effect of siPDL1/HVJ‐E, indicating that CD8+ T lymphocytes mainly mediated this therapeutic effect. We believe that this non‐replicating immunovirotherapy may be a novel therapeutic alternative to treat patients with glioblastoma.
HVJ‐E containing PD‐L1 siRNA significantly prolonged overall survival in mouse brain glioblastoma models. The therapeutic performance was mediated by antitumor immune responses via increased proportions of brain‐infiltrating CTL and a decreased rate of Treg among CD4+ T cells. This non‐replicating immunovirotherapy appears to show great promise as an attractive novel alternative to treat patients with glioblastoma.
Recent experimental data and clinical, genetic, and transcriptome evidence from patients converge to suggest a key role of interleukin-1β (IL-1β) in the pathogenesis of Kawasaki disease (KD). ...However, the molecular mechanisms involved in the development of cardiovascular lesions during KD vasculitis are still unknown. Here, we investigated intestinal barrier function in KD vasculitis and observed evidence of intestinal permeability and elevated circulating secretory immunoglobulin A (sIgA) in KD patients, as well as elevated sIgA and IgA deposition in vascular tissues in a mouse model of KD vasculitis. Targeting intestinal permeability corrected gut permeability, prevented IgA deposition and ameliorated cardiovascular pathology in the mouse model. Using genetic and pharmacologic inhibition of IL-1β signaling, we demonstrate that IL-1β lies upstream of disrupted intestinal barrier function, subsequent IgA vasculitis development, and cardiac inflammation. Targeting mucosal barrier dysfunction and the IL-1β pathway may also be applicable to other IgA-related diseases, including IgA vasculitis and IgA nephropathy.
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•IL-1β-driven increased intestinal permeability is observed in murine KD model•Blocking intestinal permeability or IgA production decreases murine KD vasculitis•IgA and IgA-C3 are observed in cardiovascular lesions of murine KD model•KD vasculitis may be a form of IgA vasculitis involving a gut-vascular axis
Kawasaki disease (KD) is the leading cause of acquired heart disease among children, and the etiology is unknown. Noval Rivas et al. demonstrate that a murine model of KD vasculitis is dependent on intestinal barrier dysfunction leading to secretory IgA leakage and IgA-C3 immune complex deposition in cardiovascular lesions.
While group-2 innate lymphoid cells (ILC2s) are highly proliferative in allergic inflammation, the removal of overactivated ILC2s in allergic diseases has not been investigated. We previously showed ...that chronic airway allergy induces "exhausted-like" dysfunctional ILC2s expressing T cell immunoreceptor with Ig and ITIM domains (TIGIT). However, the physiological relevance of these cells in chronic allergy remains elusive. To precisely identify and monitor TIGIT+ ILC2s, we generated TIGIT lineage tracer mice. Chronic allergy stably induced TIGIT+ ILC2s, which were highly activated, apoptotic, and were quickly removed from sites of chronic allergy. Transcripts from coding genes were globally suppressed in the cells, possibly due to reduced chromatin accessibility. Cell death in TIGIT+ ILC2s was enhanced by interactions with CD155 expressed on macrophages, whereas genetic ablation of Tigit or blockade by anti-TIGIT antagonistic antibodies promoted ILC2 survival, thereby deteriorating chronic allergic inflammation. Our work demonstrates that TIGIT shifts the fate of ILC2s toward activation-induced cell death, which could present a new therapeutic target for chronic allergies.
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