Notch and Tumor Immunity

Cancer immunosurveillance is critical for the elimination of neoplastic cells. In addition, recent advances in immunological checkpoint blockade drugs have revealed the importance of the immune system in cancer treatment. As a component of the immune system, CD8+ T cells have important roles in suppressing tumors. CD8+ T cells can kill tumor cells with cytotoxic molecules, such as granzymes and perforin. IFNγ, which is produced by CD8+ T cells, can increase the expression of MHC class I antigens by tumor cells, thereby rendering them better targets for CD8+ T cells. IFNγ also has crucial functions in enhancing the antitumor abilities of other immune cells. Therefore, it has been hypothesized that antitumor immunity could be improved by modulating the activity of CD8+ T cells. The Notch pathway regulates CD8+ T cells in multiple ways. It directly upregulates mRNA expression of granzyme B and perforin, enhances differentiation toward short-lived effector cells, and maintains memory T cells. Intriguingly, CD8+ T cell-specific Notch2 deletion impairs antitumor immunity, whereas the stimulation of the Notch pathway can increase tumor suppression. In this review, we will summarize the roles of the Notch pathway in CD8+ T cells and discuss issues and implications for its use in antitumor immunity

The cellular and molecular mechanism of CD4/CD8 lineage commitment

A unique feature ofαβT-cell development is the central role played by clonally distributed T-cell receptors (TCR), which are encoded by somatically rearranged gene segments that produce a diverse, non-germline encoded set of receptors. Fate determination in individual T-cells is mediated by ligand-receptor signals that arise from unprogrammed genetic interactions, under conditions in which the relevant ligand concentration and the receptor affinity are not evolutionarily controlled. A precursor T-cell with a TCR that either fails to demonstrate appreciable self-reactivity or binds with high affinity to reasonably abundant self-peptide major histocompatibility complex (MHC)-ligands will undergo apoptosis. In contrast, a precursor T-cell that shows lower affinity to moderately abundant ligands will receive suitable signals for survival and maturation. Recently, we have developed a rapid in vitro two-step organ culture system that permits homogeneous populations of non-transformed precursor T-cells to undergo selective commitment to the CD4 or CD8 lineage. Using this model, we have shown that the choice of positively selected ab T-cells between the CD4 helper and CD8 cytotoxic lineages is regulated by the TCR signaling duration in response to self-peptides bound to the MHC

ゼンシンセイ エリテマトーデス ノ ゲンイン イデンシ ノ カイメイ ト ソレ ニ モトズク シンキ チリョウホウ ノ カノウセイ

Autoimmune diseases are caused by defective genes, aberrant gene expression or regulation, and environmental factors. Autoimmune disease susceptibility is determined by the interplay of these factors, which eventually affect autoreactive lymphocyte activation status or cell death sensitivity. Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a broad variety of clinical symptoms and autoantibody production against nucleic acids, typically double-stranded DNA. Several lines of evidence indicate SLE development has a strong genetic basis. Recent studies have shown that most of the peripheral CD4+ or CD8+ T-cells have a potential to respond to self-antigens and persistence of such self antigens in vivo can provoke human or murine SLE. These recent findings in basic and clinical immunology would cause us to reconsider the importance of antigen clearance and persistence as a cause of SLE. Thus, I would like to review the lymphocyte abnormal responses seen in SLE patients from the view point of defective self-antigen clearance

Development of malaria vaccines that block transmission of parasites by mosquito vectors

Malaria is still one of the infectious diseases urgently requiring control and causes socioeconomic burdens on people residing in developing countries. Malaria vaccines are expected to control the disease. However, there is no effective vaccine available despite the intense efforts of malaria scientists. One strategy for a malaria vaccine is to prevent parasite spread by means of interfering with parasite development in mosquito vectors, which is the so-called transmission-blocking vaccine (TBV). We will here review the current progress of TBV

Preventive effect of fermented brown rice and rice bran on spontaneous type 1 diabetes in NOD female mice

Consumption of brown rice and rice bran fermented with Aspergillus oryzae (FBRA) suppresses spontaneously occurring diabetes in female NOD mouse. While control diet-fed mice showed glucosuria and hyperglycemia at around 20 week of age and the ratio reached to 57% at 30 weeks of age, the ratio did not increase in the 0.5% FBRA-containing diet-fed group. The FBRA-fed group at 30 weeks of age kept higher ratio of intact islets and showed significantly lower insulitis score compared to the control diet group, with dose-dependency from 0.25% to 0.5% dietary concentration of FBRA. The percentage of diabetic mice was significantly lower at 24 weeks of age as compared to the control group (p = 0.01, log rank test). These results indicate that the suppressive effects of dietary administration of 0.5% FBRA in delaying the spontaneous onset of diabetes in NOD mice is probably achieved by maintaining the number of intact islets

Stimulation of the farnesoid X receptor promotes M2 macrophage polarization

FXR is a key molecule that modulates anti-inflammatory activity in the intestinal-liver axis. Although FXR has pleiotropic functions including regulation of liver inflammation and activation of macrophages, it remains unclear whether it is involved in macrophage polarization. In this paper we demonstrated that stimulation of macrophages derived from the bone marrow using an FXR agonist activated polarization toward M2 but not M1 macrophages. The treatment of mice with chitin skewed macrophage polarization towards M2 macrophages, while co-treatment with an FXR agonist further promoted the polarization toward M2 macrophages in vivo. This skewed polarization towards M2 macrophages by an FXR agonist was accompanied by increased expression of signaling molecules related to the retinoic acid receptor. Inhibition of the retinoic acid receptor suppressed FXR agonist-mediated M2 macrophage polarization, indicating that this polarization was, at least, partly dependent on the retinoic acid receptor pathway. These data demonstrate that FXR has a role in polarization toward M2 macrophages and suggest a possible therapeutic potential of FXR agonists in M2 macrophage-related conditions

Cytokines and NLRC4-Dysregulated Diseases

The NLRC4 inflammasome assembles in response to detection of bacterial invasion, and NLRC4 activation leads to the production of IL-1β and IL-18 together with pyroptosis-mediated cell death. Missense activating mutations in NLRC4 cause autoinflammatory disorders whose symptoms are distinctly dependent on the site of mutation and other aspects of the genetic background. To determine the involvement of IL-1β and IL-18 in the inflammation induced by NLRC4 mutation, we depleted IL-1β, IL-18, or both cytokines in Nlrc4-transgenic mice in which mutant Nlrc4 is expressed under the MHC class II promoter (Nlrc4-H443P-Tg mice). The deletion of the Il1b or Il18 gene in Nlrc4-H443P-Tg mice reduced the neutrophil numbers in the spleen, and mice with deletion of both genes had an equivalent number of neutrophils compared to wild-type mice. Deletion of Il1b ameliorated but did not eliminate bone marrow hyperplasia, while mice deficient in Il18 showed no bone marrow hyperplasia. In contrast, tail bone deformity remained in the presence of Il18 deficiency, but Il1b deficiency completely abolished bone deformity. The decreased bone density in Nlrc4-H443P-Tg mice was counteracted by Il1b but not Il18 deficiency. Our results demonstrate the distinct effects of IL-1β and IL-18 on NLRC4-induced inflammation among tissues, which suggests that blockers for each cytokine should be utilized depending on the site of inflammation

Divergent Changes in the Sensitivity of Maturing T Cells to Structurally Related Ligands Underlies Formation of a Useful T Cell Repertoire

AbstractCD4+CD8+ thymocyte differentiation requires TCR signaling induced by self-peptide/MHC ligands. Nevertheless, the resulting mature T cells are not activated by these self-complexes, whereas foreign ligands can be potent stimuli. Here, we show that the signaling properties of TCR change during thymocyte maturation, differentially affecting responses to related peptide/MHC molecule complexes and contributing to this discrimination. Weak agonists for CD4+CD8+ thymocytes lose potency during development, accompanied by a change in TCR-associated phosphorylation from an agonist to a partial agonist/antagonist pattern. In contrast, sensitivity to strong agonists is maintained, along with full signaling. This yields a mature T cell pool highly responsive to foreign antigen while possessing a wide margin of safety against activation by self-ligands

Treatment with DHA/EPA ameliorates atopic dermatitis-like skin disease by blocking LTB4 production

Atopic dermatitis (AD) is caused by both dysregulated immune responses and an impaired skin barrier. Although leukotriene B4 (LTB4) is involved in tissue inflammation that occurs in several disorders, including AD, therapeutic strategies based on LTB4 inhibition have not been explored. Here we demonstrate that progression of an AD-like skin disease in NC/Nga mice is inhibited when docosahexaenoic acid (DHA)/eicosapentaenoic acid (EPA) is administered together with FK506. Treatment with DHA/EPA and FK506 decreases the clinical score of dermatitis in NC/Nga mice and lowers local LTB4 concentrations. The treatment also suppressed the infiltration of T cells, B cells, eosinophils and neutrophils, and promoted reduced serum IgE levels. Secretion of IL-13 and IL-17A in CD4+ T cells was lower in DHA/EPA- and FK506-treated mice than in mice treated with FK506 alone. The inhibition of disease progression induced by DHA/EPA was reversed by local injection of LTB4, suggesting that the therapeutic effect of DHA/EPA is LTB4-dependent. Our results demonstrate that treatment of AD with DHA/EPA is effective for allergic skin inflammation and acts by suppressing LTB4 production

ナゼ アレルギー シッカン ワ ゾウカ シテ イルノカ : メンエキガク ノ タチバ ヨリ

Type I allergic diseases, such as rhinitis, pollinosis and bronchial asthma, are mediated by Th2-type helper T cell induction, specific IgE antibody production and mast cell activation. Increases of these allergic diseases in recent years might be caused by skewed differentiation of T cells toward Th2 cells by some environmental factors including diesel exhaust particles and decreases of virus and bacteria infection in childhood. The decrease of parasite infection is also thought to affect the susceptibility against allergic diseases by eliciting polyclonal IgE production that suppresses mast cell activation. Important clues for prevention and therapy of the allergic diseases would be derived from further investigations of the relationship between the diseases and these environmental factors