International immunology最新文献

Cancer progression can be understood as a process of diversification and selection (the evolutionary theory of cancer). The immune system also plays a critical role in this process of diversification and selection. The cancer immunoediting hypothesis provides a partial explanation of this evolutionary process; immune-evading cancer clones with genomic and/or epigenomic alterations are selected under the pressure of immune surveillance and immunosuppressive mechanisms are equipped, leading to the development of clinically apparent cancers. Indeed, inflammatory cancers equip immunosuppressive mechanisms in response to the pressure of the immune system. However, recent studies focusing on human cancers have revealed that certain non-inflammatory cancers, which often harbor a single-driver oncogenic mutation, are equipped with immunosuppressive machinery sufficient to evade immune surveillance at the time of malignant transformation. The sequential model of the cancer immunoediting hypothesis is inadequate to explain the development of these non-inflammatory cancers, highlighting the need for a novel concept that can explain their co-evolutionary processes. Moreover, inhibition of oncogenic signaling by specific driver oncogenes has been shown not only to kill cancer cells but also to augment antitumor immunity, suggesting the potential for the advent of molecularly targeted reagents with a variety of immunomodulatory functions from the perspective of personalized therapies. Here, we discuss the processes by which cancer cells and the immune system co-evolve to establish clinically apparent cancers, thereby introducing a new concept of 'immunogenomic cancer evolution', that provides a rationale for the potential of 'immunogenomic cancer precision medicine'.

Two major macrophage populations in the steady-state liver, resident Kupffer cells (KCs) and monocyte-derived macrophages (MoMFs), contribute crucially to the unique physiological functions of the organ. Much remains to be learned, however, about how the differentiation and functions of these cell populations are regulated. We found here that Ly6C-MHCII+ MoMFs were severely reduced in mice lacking interferon (IFN) regulatory factor-2 (IRF-2) (Irf2-/- mice) but restored to the normal frequencies by introducing type I IFN receptor deficiency, indicating that IRF-2 supports MoMF differentiation through attenuating excess type I IFN signals. On the other hand, Irf2-/- KCs developed normally but lacked MHC class II (MHCII) expression. Similar MHCII deficiency in KCs in Il15-/- and Ifng-/- but not Rag1-/- mice pointed to the role for NK cell-derived IFN-γ. Indeed, MHCII expression on resident KCs in Ifng-/- mice was recovered via wild-type NK cells that circulated upon parabiosis as well as by administration of IFN-γ. In contrast, parabiotic restoration of NK cell deficiency in Irf2-/- mice failed to elevate MHCII expression on KCs. Furthermore, Irf2-/- KCs required several times higher amounts of IFN-γ to upregulate MHCII expression than Ifng-/- KCs. Thus, IRF-2 maintains steady-state MHCII expression on KCs by potentiating IFN-γ responses of KCs. Collectively, our current study revealed that IRF-2 plays critical roles in the establishment of the steady state hepatic macrophage system through negative and positive regulation of type I IFN and IFN-γ signaling, respectively.

Invariant natural killer T (iNKT) cells differentiate into at least three distinct subsets within the thymus, with each subset's frequency varying considerably among mouse strains; however, the molecular mechanisms involved remain unclear. We herein report that iNKT cell lineage diversity results from the significant expansion of iNKT2 cells with limited T cell receptor (TCR) diversity in BALB/c mice and the selection of iNKT1 cells with significantly diverse TCRs in B6 mice. Furthermore, signaling lymphocytic-activation molecule family 6 (SLAMF6) expression on immature thymocytes significantly differs among mouse strains, with the low expression of SLAMF6 on BALB/c immature thymocytes resulting in high "basal TCR signaling" in preselected DP thymocytes, associated with iNKT cell expansion. Our data suggest that the expression level of SLAMF6 on immature thymocytes affects basal TCR signaling in preselected DP thymocytes, which may influence thymocyte development in a T-cell subset.

Immune cells are classified into adaptive and innate immune cells. Adaptive immune cells-i.e. T cells and B cells-respond to pathogens in an antigen-specific manner and then provide immunological memory, contributing to long-term host defense against reinfection. In contrast, innate immune cells promptly respond to pathogens, but they are short-lived and have been thought not to contribute to immunological memory. Natural killer (NK) cells are lymphocytes essential for controlling viral infections and cancer. NK cells-which have traditionally been classified as innate immune cells-have recently been revealed as being capable of differentiating into memory NK cells, thus participating in immunological memory, formerly considered to be restricted to adaptive immune cells. Like memory T and B cells, memory NK cells (i) can be long-lived; (ii) display distinct phenotypes from naïve and activated NK cells; (iii) show augmented cellular functions, as compared with naïve NK cells; (iv) have secondary proliferation capacity; and (v) confer an improved host defense when transferred to naïve recipients. Therefore, at least in a broad sense, they fulfill the definition of immunological memory. In this article, I provide an overview of NK cell memory and recent research trends regarding this phenomenon.

It is well known that regulatory B cells (Breg), especially IL-10-producing regulatory cells (B10), play an important role in immune regulation during inflammatory and infectious diseases. Although it has been revealed that the immune regulatory function of B10 can be exerted through cognate cell-cell contact with T cells, more research is needed to delineate its impact on other key cellular immune components within the immune microenvironment. In this study, we evaluated the effect of B10 on the phenotypic change of macrophages and their pro-resolving functional activities using various co-culture systems. The roles of cell-cell contact and the IL-10 secretion by B10 on macrophage differentiation and function were determined. Splenocyte-derived B10 cells from wild-type or IL-10 knockout (KO) mice were co-cultured with RAW 264.7 cells in the presence or absence of trans-well inserts. Macrophage polarization, programmed cell death 1 (PD-1) expression, production of specialized pro-resolving mediators (SPMs), and phagocytic activity were evaluated. The results showed that direct B10-macrophage co-culture enhanced the macrophage polarization towards a pro-resolving phenotype and their PD-1 expression, which was diminished when the cultured B10 and macrophages were separated by trans-well inserts, or when B cells from IL-10 KO mice were used for the co-culture. In addition, B10 was found to promote the release of specific SPM [resolvin D series 5 (RvD5)] and phagocytic activity by macrophages after co-culture. These effects were compromised in trans-well co-culture or co-cultures with IL-10-deficient B cells. Our results suggest that B10 promotes pro-resolving macrophage differentiation and function through direct cell-cell contact and IL-10 secretion.

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.