International immunology最新文献

Proteasomes are essential molecular complexes that regulate intracellular protein homeostasis by selectively degrading ubiquitinated proteins. Genetic mutations in proteasome subunits lead to proteasome-associated autoinflammatory syndromes (PRAAS) characterized by autoinflammation, partial progressive lipodystrophy, and, in certain cases, immunodeficiency. However, the molecular mechanisms by which proteasome dysfunction results in these phenotypes remain unclear. Here, we established a mouse model carrying a mutation in β5i (encoded by Psmb8) along with T-cell-specific β5 (encoded by Psmb5) deficiency (KIKO mice). The KIKO mice presented severe loss of mature T cells in the spleen but not in the thymus, with reduced proteasome activity leading to the accumulation of ubiquitinated proteins. The CD4+ T cells of KIKO mice presented impaired proliferative activity with cell cycle arrest in the G0/G1 phase following T cell receptor (TCR) engagement. T cells from KIKO mice underwent rapid cell death through apoptosis, as treatment of T cells with the caspase inhibitor Z-Val-Ala-Asp(Ome)-fluoromethylketone (Z-VAD-FMK) rescued cell viability. Moreover, proteasome dysfunction induced apoptosis in T cells without affecting either mitochondrial functions or endoplasmic reticulum (ER) stress responses. Thus, our data provide insight into the molecular mechanisms underlying not only immunodeficiency in PRAAS patients but also T-cell deficiency associated with other disorders.

Chronic kidney disease is a global health problem with high morbidity and mortality rates. Acute kidney injury substantially increases the risk of chronic kidney disease progression, particularly in the elderly, partly because of prolonged inflammation that exacerbates kidney fibrosis and dysfunction. Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates that develop in non-lymphoid organs during chronic inflammation, such as autoimmune diseases, cancers, and age-related inflammation. Age-dependent TLS formation is observed in various organs, such as the kidneys, bladder, lacrimal glands, and liver, potentially contributing to age-related disorders, including chronic kidney disease progression after acute kidney injury. TLSs contain heterogeneous cell populations, such as T cells, B cells, pro-inflammatory fibroblasts, and blood and lymphatic vessels, which orchestrate TLS development and expansion through intensive cell-cell interactions. Pro-inflammatory fibroblasts within TLSs drive TLS formation by producing various chemokines and cytokines that recruit and activate immune cells. Additionally, the CD153-CD30 signaling pathway between senescence-associated T cells and age-associated B cells, both of which increase with age, are essential for renal TLS maturation and expansion, which could be a promising therapeutic target in kidney injury in aged individuals. TLSs also develop in human kidney diseases, such as various glomerulopathies, transplanted kidneys, and renal cell carcinomas, thereby influencing patient outcomes. This review highlights the recent advances in our understanding of the cellular and molecular mechanisms underlying TLS development and pathogenicity, with a focus on age-dependent TLSs in the kidneys. Furthermore, the clinical relevance of TLSs in human kidney diseases is discussed.

Germinal center (GC) reactions are tightly regulated to generate high-affinity antibodies. Although IL10+ Foxp3- follicular T cells have recently been described as contributing to the suppression of GC reactions, their differentiation, localization, and heterogeneity remain incompletely understood. Additionally, it remains unclear whether IL10+ Foxp3- follicular T cells represent a transient status or an independent subset. To address these gaps, we performed integrative single-cell analysis of transcriptomes, epigenomes, surface proteomes, and TCR repertoires in human tonsillar CD4+ T cells. Unbiased clustering revealed IL10+ Foxp3- follicular T cells as a transcriptionally and epigenetically unique subset. This subset exhibited features of both T follicular helper (Tfh) and T regulatory type 1 (Tr1) cells, and accordingly, hereafter, we call them T follicular regulatory type 1 (Tfr1) cells. Analysis using imaging mass cytometry and spatial RNA-TCR sequencing demonstrated their presence within GCs in humans. Bioinformatic analysis suggested that Tfr1 cells differentiate from GC-Tfh cells upon strong TCR stimulation, a finding corroborated by mouse in vivo experiments and time-series single-cell RNA-TCR sequencing of human in vivo CD4+ T cells. Of note, our bioinformatic analysis suggested that Tfr1 cells receive strong TCR signals from ICOS-Lhigh GC-B cells, likely representing high-affinity GC-B cells. Finally, we show that Tfr1 cells acquire a resident memory phenotype following an effector phase. Together, our findings suggest that high-affinity ICOS-Lhigh GC-B cells transform follicular T cells from GC-Tfh cells to Tfr1 cells, which likely become memory cells and reside in the lymphoid organ to support effective antibody production.

Ulcerative colitis and Crohn's disease, the principal forms of inflammatory bowel disease (IBD), are chronic relapsing inflammatory disorders of the gastrointestinal tract. The incidence and prevalence of IBD have been increasing worldwide, but their etiology remains largely unknown. Although anti-TNF agents can be highly effective in IBD patients, 10%-40% of patients do not respond to primary anti-TNF therapy. Furthermore, anti-TNF therapy for IBD does not prevent the incidence and progression of fibrosis. A growing body of evidence suggests that IBD pathogenesis is associated with epithelial barrier dysfunction, inappropriate immune responses to luminal microorganisms, and environmental factors as well as host genetics. Recently, a variety of mesenchymal stromal cell populations, including fibroblasts and myofibroblasts, have been characterized in individual tissues under homeostatic and inflammatory conditions. The compositions of fibroblasts and myofibroblasts are altered in the intestinal mucosa of IBD patients, and diverse properties of these cells, such as the production of pro-inflammatory cytokines and extracellular matrix components, are remodeled. Several studies have demonstrated that IBD-specific fibroblasts are involved in anti-TNF therapy refractoriness. Therefore, a better understanding of the interaction among fibroblasts, epithelial cells, immune cells, and microbes associated with the maintenance and perturbation of intestinal homeostasis may facilitate the identification of novel therapeutic targets for IBD. This review presents the key findings obtained to date regarding the pathological and homeostatic mechanisms by which functionally distinct fibroblasts and myofibroblasts regulate epithelial barrier integrity, immunity, and tissue regeneration in health and in gastrointestinal disorders.

Neural signaling regulates various reactions in our body including immune responses. Neuromodulation of this signaling using artificial neural activation and/or suppression is a potential treatment for diseases and disorders. We here review neural signaling regulating the immune system, with a special focus on the gateway reflex. The gateway reflex is a novel neuro-immune crosstalk mechanism that regulates tissue-specific inflammatory diseases. We have discovered six gateway reflexes so far; all are induced by environmental or artificial stimulations including gravity, electrical stimulation, pain sensation, stress, light, and inflammation in joints. In the presence of increased autoreactive T cells in the blood, such stimulation activates specific neural signaling to release noradrenaline (NA) from the nerve endings at specific blood vessels in the central nervous system. NA activates the interleukin-6 (IL-6) amplifier, which leads to the hyper-activation of nuclear factor-kappa B (NF-κB) in non-immune cells, resulting in the formation of a gateway. This gateway allows autoreactive T cells and other immune cells to accumulate in the target tissue to induce inflammatory diseases. In gateway reflexes induced by stress or remote inflammation, adenosine triphosphate (ATP) secreted from inflammation sites activates specific neural pathways, resulting in organ dysfunction and inflammation in other tissues, suggesting that the gateway reflex regulates tissue-specific inflammatory diseases by bidirectional crosstalk between the neural and immune systems. We also discuss other cases of neural signaling including the inflammatory reflex.

Despite the high effectiveness of the coronavirus disease 2019 (COVID-19) mRNA vaccines, both immunogenicity and reactogenicity show substantial interindividual variability. One key challenge is predicting high and low responders using easily measurable parameters. In this study, we performed multivariate linear regression analysis, which allows adjustment for confounding, to explore independent predictive factors for antibody responses. Using data from 216 healthy vaccinated donors aged 23-81 years, we evaluated baseline characteristics, prevaccination blood and T-cell phenotypes, and post-vaccination T-cell responses as variables, with anti-receptor-binding domain (RBD) immunoglobulin G (IgG) titers following two doses of BNT162b2 vaccination as the primary outcome. Consistent with previous reports, higher age, a history of allergic disease, and autoimmune disease were associated with lower peak IgG titers. Additionally, the frequencies of interferon-γ+ spike-specific CD4+ T cells (T-cell response) following the first vaccination strongly correlated with higher IgG responses, while those of pre-existing spike-reactive T cells showed no association with peak IgG titers. Furthermore, we identified lower percentages of naïve CD8+ T cells, lower hemoglobin levels, lower lymphocyte counts, and higher mean corpuscular volume as independent pre-vaccination predictors of lower peak IgG levels. Notably, the frequency of naïve CD8+ T cells showed a positive correlation with the peak IgG levels even in univariate analysis. These findings contribute to the individualized prediction of mRNA vaccine efficacy and may provide insights into the mechanisms underlying individual heterogeneity in immune responses.

Intracerebral inflammation and brain swelling often worsen the functional prognosis of stroke patients. Post-stroke inflammation is resolved by the removal of inflammatogenic damage-associated molecular patterns (DAMPs) through macrophage scavenger receptor 1 (MSR1); however, therapeutics promoting MSR1 expression efficiently have not been developed. We identified ETS2 as a transcription factor that promoted MSR1 expression in myeloid cells by epigenetic molecular screening. Increased Ets2 expression in macrophages enhanced MSR1 expression and the internalization of peroxiredoxins (PRXs), pivotal inflammatogenic DAMPs in ischemic stroke. By evaluation of chemicals inducing Ets2 expression, we discovered that zoledronic acid increased Ets2 and Msr1 expression in macrophages. Post-stroke administration of zoledronic acid significantly suppressed cerebral inflammation by increasing MSR1 expression in infiltrating myeloid cells, attenuating ischemic neuronal injury in a myeloid Ets2-dependent manner. Thus, epigenetic molecular screening that enhances MSR1 expression is a useful approach to developing therapeutics that improve functional prognosis after ischemic stroke.

Monocytes recruited to inflamed tissues differentiate into macrophages, contributing to the resolution of inflammation and tissue repair. However, the mechanisms underlying the development, differentiation, and maturation of these monocyte-derived macrophages (MOMs) remain incompletely understood. Here, we demonstrate that TGFβ-activated kinase 1 (TAK1), a key signaling mediator downstream of various receptors including cytokine receptors and Toll-like receptors, is essential for MOM development. In a zymosan-induced model of acute sterile peritonitis, mice with myeloid-specific deletion of TAK1 exhibited a severe impairment in MOM development within the peritoneal cavity, in contrast to control mice. Blocking death-receptor signaling with neutralizing-antibodies facilitated the recovery of MOM development in these mice, albeit to a limited extent. We identified a transient population of immediate macrophage precursors differentiating from infiltrating monocytes in the peritoneal cavity. Notably, TAK1-deficient macrophage precursors displayed marked susceptibility to cell death, possibly due to a previously unrecognized mechanism distinct from well-characterized cell death pathways. These findings establish TAK1 as a critical regulator of MOM development and uncover a novel survival mechanism in the macrophage precursors during inflammation.

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 antibody, 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 antitumor immunity collectively enhance ICB cancer immunotherapy. Our study demonstrates the potential of combining Tal-PDT with ICB therapy for clinical applications.

Systemic lupus erythematosus 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 an endosomal single-stranded RNA sensor [Toll-like receptor 7 (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 (New Zealand Black/New Zealand White F1) 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 monocytes into glomeruli. Compared to their splenic counterparts, glomerular macrophages produced IL-1β in a TLR7-dependent manner. In addition, single-cell RNA sequencing 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 accelerate the progression of glomerulonephritis in NZBWF1 mice.