International immunology最新文献

The milky spots (MS) are structures found in the omentum of humans and other vertebrates, representing a fraction of the lymphomyeloid tissue associated with the celom. They majorly consist of B lymphocytes, T lymphocytes, and macrophages. Also found in smaller quantities are mesothelial, stromal, dendritic, and rare mast cells. In an experimental model of Schistosoma mansoni infection, there is significant activation of the omentum and MS, which exhibit numerous eosinophils. Despite being described for many years, the complete profile of cells found in MS and their functions remains largely unexplored. Here, we evaluate the leukocyte populations of the MS in homeostasis and a murine model of S. mansoni infection. The histopathological characterization, phenotypic profile analysis, and characterization of the eosinophilic potential of progenitors and precursors comparing the MS with the spleen and bone marrow showed significant activation of MS in infected mice, with changes in the profile over the analyzed times, showing signs of migration and activation of eosinophils, with local eosinopoiesis and maintenance of the eosinophilic population. In naive mice, B1a and B1b cells make up only a small fraction of B lymphocytes. However, B1b cells expand significantly during infection, peaking at 60 days post-infection (DPI) before stabilizing by 90 DPI. B1a cells also increase initially but decrease over time. The behavior of MS differs from other primary and secondary lymphoid organs, acting as a central lymphoid organ in cavity immunity.

The cancer driver mutation L265P MyD88 is found in approximately 30 % of cases in the activated B cell-like subgroup of diffuse large B cell-like lymphoma (ABC DLBCL). L265P MyD88 forms a complex with TLR9 and IgM, referred to as the My-T-BCR complex, to drive proliferation. We here show that the B cell surface molecules CD19 and CD20 enhance proliferation mediated by the My-T-BCR complex. Using the IL-3-dependent Ba/F3 line transduced to express the IgM complex (IgM, CD79a, and CD79b) and TLR9, we observed proliferation in the presence of anti-IgM antibody and the TLR9 ligand CpG-B. TLR9 was constitutively associated with IgM and L252P MyD88. CD19 promoted proliferation with anti-IgM and CpG-B specifically in L252P MyD88-expressing Ba/F3 cells, while CD20 enhanced the proliferation in both wild-type- and L252P MyD88-expressing Ba/F3 cells. Additionally, CD20 uniquely enabled IgM-mediated proliferation in L252P MyD88-expressing Ba/F3 cells. Although CpG-B was not required for this proliferation, TLR9 expression remained indispensable. In the ABC DLBCL line TMD8, anti-IgM Ab mediated growth was impaired by the lack of CD20 and CD19 or of TLR9. Mechanistically, CD19 promoted IgM-dependent AKT phosphorylation, whereas CD20 increased expression of cell surface IgM, thereby enhancing the formation of the IgM-TLR9 complex. These findings suggest that CD19 and CD20 differentially contribute to the proliferation driven by the My-T-BCR complex.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies and damage to multiple organs. Glomerulonephritis, a manifestation involving glomerular deposition of immune complexes and complement components, significantly contributes to disease morbidity. Although the endosomal single-stranded RNA sensor TLR7 is known to drive glomerulonephritis by promoting autoantibody production in B cells, the contribution of macrophage TLR7 responses to glomerulonephritis remains poorly understood. Here, we have examined Tlr7‒/‒ NZBWF1 mice and found that TLR7-deficiency ameliorates lupus nephritis by abolishing autoantibody production against RNA-associated antigens, C3 deposition, and macrophage accumulation in glomeruli. Furthermore, TLR7 signaling increased CD31 expression on glomerular endothelial cells and Ly6Clow macrophages but not on T and B cells, suggesting that CD31 mediates TLR7-dependent migration of monocyte into glomeruli. Compared to their splenic counterparts, glomerular macrophages produced IL-1β in a TLR7-dependent manner. In addition, single cell RNA sequencing (scRNA-seq) of glomerular macrophages revealed that TLR7 signaling induced expression of lupus associated genes including those encoding Chitinase 3 like 1, ferritin heavy chain 1, IKKε, and complement factor B (CfB). Although serum CfB did not increase in NZBWF1 mice, TLR7-dependent CfB protein expression was detected in glomerular macrophages. In addition, TLR7 signaling promoted C3 cleavage and deposition predominantly on mesangial cells. These findings suggest that TLR7 responses in glomerular macrophages accelerates the progression of glomerulonephritis in NZBWF1 mice.

Photodynamic therapy (PDT), a local cancer treatment using photosensitizers, has been reported to enhance antitumor immune responses by inducing immunogenic cell death. Although several studies have demonstrated the synergistic antitumor effects of PDT and immune checkpoint blockage (ICB), the detailed underlying mechanisms remain poorly understood. In this study, we investigated the immunological effects of PDT with talaporfin (Tal-PDT), a clinically approved photosensitizer, using bilateral tumor-bearing mouse models. Treatment with Tal-PDT on the tumor on one side of the mouse resulted in tumor growth inhibition on the untreated opposite side. This phenomenon, accompanied by tumor antigen-specific immune reactions, is indicative of an abscopal effect. When combined with anti PD-L1 Ab, synergistic antitumor effects were observed on both the laser-treated and untreated sides. Mechanistically, Tal-PDT enhanced the induction of XCR-1+ dendritic cells in the proximal draining lymph node likely through the induction of ferroptosis in tumor cells. This, in turn, led to the systemic generation of precursor-exhausted CD8+ T cells. Moreover, talaporfin was selectively incorporated into tumor cells rather than into tumor-infiltrating T cells in vivo, leading to targeted tumor killing while preserving T cells. These beneficial effects of Tal-PDT on anti-tumor immunity collectively enhance ICB cancer immunotherapy. Our study demonstrates the potential of combining Tal-PDT with ICB therapy for clinical applications.

Since the first approval of an immune-checkpoint inhibitor, we have witnessed the clinical success of cancer immunotherapy. Adoptive T-cell therapy with chimeric antigen-receptor T (CAR-T) cells has shown remarkable efficacy in hematological malignancies. Concurrently with these successes, the cancer immunoediting concept that refined the cancer immunosurveillance concept underpinned the scientific mechanism and reason for past failures, as well as recent breakthroughs in cancer immunotherapy. Now, we face the next step of issues to be solved in this field, such as tumor heterogeneity, the tumor microenvironment, the metabolism of tumors and the immune system, and personalized approaches for patients, aiming to expand the population benefitted by the therapies.

Glomerulonephritis (GN) is a group of heterogeneous immune-mediated kidney diseases that causes inflammation within the glomerulus. Autoantibodies (auto-Abs) are considered to be central effectors in the pathogenesis of several types of GN. Immunoglobulin A nephropathy (IgAN) is the most common GN worldwide and is characterized by the deposition of IgA in the glomerular mesangium of the kidneys, which is thought to be mediated by immune complexes containing non-specific IgA. However, we recently reported that IgA auto-Abs specific to mesangial cells (anti-mesangium IgA) were found in the sera of gddY mice, a spontaneous IgAN model, and patients with IgAN. We identified two autoantigens (β2-spectrin and CBX3) that are selectively expressed on the mesangial cell surface and targeted by anti-mesangial IgA. Our findings redefined IgAN as a tissue-specific autoimmune disease. Regarding the mechanisms of production of anti-mesangium IgA, studies using gddY mice have revealed that the production of anti-CBX3 IgA is induced by particular strains of commensal bacteria in the oral cavity, possibly through their molecular mimicry to CBX3. Here, we discuss a new concept of IgAN pathogenesis from the perspective of this disease as autoimmune GN caused by tissue-specific auto-Abs.

The transcription factor T-bet is essential for the anti-tumor effector function of natural killer (NK) cells, but the mechanism regulating its expression in NK cells remains unclear. In this study, we aimed to identify an NK cell-intrinsic regulator that controls T-bet expression. Using T-bet-luciferase reporter assay screening, we identified a protein phosphatase inhibitor as a potential activator of T-bet expression. A series of protein phosphatase 2A (PP2A)-specific inhibitors (PP2Ai) or PP2A siRNA induced the expression of T-bet. In PP2Ai-treated mice, the expression of T-bet and its downstream effector molecules, granzyme B and IFN-γ, was also upregulated in NK cells. Mechanistically, PP2Ai increased the phosphorylation of mTOR and ribosomal protein S6 in NK cells, and mTOR inhibitor canceled the effects of PP2Ai in NK cells. Importantly, NK cells isolated from PP2Ai-treated mice showed higher cytotoxicity and IFN-γ production; therefore, they increased the anti-tumor effector function of NK cells. Accordingly, PP2Ai treatment inhibited lung metastasis of B16 melanoma by NK cell- and mTOR-dependent mechanisms. These results suggest that PP2A negatively regulates NK cell T-bet expression and effector function by an mTOR-dependent mechanism.

Regulatory T cells (Tregs) are a specialized subset of CD4+ T cells essential for the maintenance of immune homeostasis and prevention of autoimmunity. Treg lineage and functions are programmed by the X-chromosome encoded transcription factor forkhead box P3 (FOXP3). In humans, multiple FOXP3 isoforms are generated through alternative splicing. A full-length isoform containing all coding exons (FOXP3-FL) and a version lacking the second exon (FOXP3-ΔE2) are the predominant FOXP3 isoforms. Additionally, there are two minor isoforms lacking either exon 7 (FOXP3-ΔE7) and both exons 2 and 7 (FOXP3-ΔE2ΔE7). Although healthy humans express approximately equal levels of the FOXP3-FL and FOXP3-ΔE2 isoforms, sole expression of FOXP3-ΔE2 results in the development of a systemic autoimmune disease that resembles immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. These clinical observations strongly suggest functional defects in suppression by Tregs programmed by the FOXP3-ΔE2 isoform. Work from the past two decades has provided phenotypic and functional evidence of differences between Tregs programmed by the FOXP3-FL, FOXP3-ΔE2, and FOXP3-ΔE7 isoforms. In this review, we discuss the discovery of the FOXP3 isoforms, differences in the phenotype and function of Tregs programmed by different FOXP3 isoforms, and the role that these isoforms are known to play in autoimmunity.

The immune system exhibits spatial diversity in in vivo tissues. Immune cells are strategically distributed within tissues to maintain the organ integrity. Advanced technologies such as intravital imaging and spatial transcriptomics have revealed the spatial heterogeneity of immune cell distribution and function within organs such as the liver, kidney, intestine, and lung. In addition, these technologies visualize nutrient and oxygen environments across tissues. Recent spatial analyses have suggested that a functional immune niche is determined by interactions between immune and non-immune cells in an appropriate nutrient and oxygen environment. Understanding the spatial communication between immune cells, environment, and surrounding non-immune cells is crucial for developing strategies to control immune responses and effectively manage inflammatory diseases.

Onco-immunotherapy via blocking checkpoint inhibitors has revolutionized the treatment-landscape of several malignancies, though not in the metastatic castration-resistant prostate cancer (PCa) owing to an immunosuppressive and poorly immunogenic "cold" tumor microenvironment (TME). Turning up the heat of such a cold TME via triggering innate immunity is now of increasing interest to restore immune-surveillance. Retinoic acid-inducible gene-I (RIG-I)-like receptors (RLRs) are cytosolic innate-sensors that can detect exogenous RNAs and induce type-I interferons and other pro-inflammatory signaling. RIG-I activation is suggested to be a valuable addition to the treatment approaches for several cancers. However, the knowledge about RIG-I signaling in PCa remains elusive. The present study evaluated the expression of two important RLRs, RIG-I and melanoma differentiation-associated protein 5 (MDA5), along with their downstream partners, mitochondrial antiviral-signaling protein (MAVS) and ERA G-protein-like 1 (ERAL1), during PCa progression in the transgenic adenocarcinoma of mouse prostate (TRAMP) model. The early stage of PCa revealed a significant increment in the expression of RLRs but not MAVS. However, the advanced stage showed downregulated RLR signaling. Further, the therapeutic implication of 5'ppp-dsRNA, a synthetic RIG-I agonist and Bcl2 gene silencer, has been investigated in vitro and in vivo. Intra-tumoral delivery of 5'ppp-dsRNA regressed tumor growth via triggering tumor cell apoptosis, immunomodulation, and inducing phagocytic "eat me" signals. These findings highlight that, for the first time, RIG-I activation and Bcl-2 silencing with 5'ppp-dsRNA can serve as a potent tumor-suppressor strategy in PCa and has a significant clinical implication in transforming a "cold" TME into an immunogenic "hot" TME of PCa.