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

Welcome "Home," Students: The Reintegration of Kikoku Shijo in the Japanese Education System

Honors (Bachelor's)International StudiesUniversity of Michiganhttps://deepblue.lib.umich.edu/bitstream/2027.42/139664/1/tsuniw.pd

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

Loss-of-function mutation in toll-like recptor 4 prevents diet-induced obesity and insulin resistence

Orientador: Mario Jose Abdalla SaadTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias MedicasResumo: Estudos recentes demonstram que a obesidade está associada com a resistência à insulina e com um estado de inflamação crônica subclínica. Os ¿Toll-Like Receptors¿ (TLRs) têm um papel fundamental na ativação do sistema imune através do reconhecimento de antígenos de microorganismos. O TLR4 é um subtipo de TLRs que é ativado pelo lipopolissacarídeo de bactérias gram-negativas e por outros agonistas, como os ácidos graxos saturados. A ativação do TLR4 estimula vias inflamatórias relacionadas à indução de resistência à insulina, como a JNK e a IKKß. Neste estudo, demonstrou-se que camundongos C3H/HeJ, que apresentam uma mutação inativadora do TLR4, estão protegidos da obesidade e da resistência à insulina induzidas por dieta hiperlipídica. Além disso, músculos sóleos isolados de camundongos C3H/HeJ estão protegidos da resistência à insulina induzida por ácidos graxos. Camundongos C3H/HeJ tratados com dieta hiperlipídica (DH) apresentam um menor ganho de peso, maior tolerância à glicose e maior sensibilidade à insulina em relação aos controles em DH. A análise morfométrica do tecido adiposo evidenciou que os adipócitos dos camundongos C3H/HeJ em DH são 30% menores em relação aos adipócitos dos camundongos controle tratados com a mesma dieta. Foi evidenciada uma maior fosforilação em tirosina do IRS-1 e maior fosforilação da Akt, após estímulo com insulina, em músculo, tecido adiposo e fígado de camundongos C3H/HeJ tratados com DH em relação aos controles. Observou-se uma maior ativação da JNK, da IKKß e da iNOS em músculo, tecido adiposo e fígado de animais controle tratados com DH quando comparado com camundongos C3H/HeJ tratados com a mesma dieta. O tratamento com palmitato reduziu a captação de glicose e a síntese de glicogênio em 40-50% em músculo sóleo isolado de camundongos controle, mas este efeito não foi observado em músculo sóleo isolado de camundongos C3H/HeJ. Em resumo, o nosso estudo demonstra que a inativação do TLR4 previne a obesidade induzida por dieta, a ativação da IKKß, da JNK, a resistência à insulina em camundongos em DH, além da resistência à insulina induzida por palmitato em músculo isolado. O estudo sugere que o TLR4 tem um papel importante na interligação entre o sistema imune inato e a resistência à insulina, sendo um possível alvo terapêutico para a obesidade, resistência à insulina e diabetes mellitus tipo 2Abstract: Obesity is associated with insulin resistance and a state of abnormal inflammatory response. The Toll-like receptor 4 (TLR4) has an important role in inflammation and immunity and its expression has been reported in most tissues of the body, including the insulin-sensitive ones. Since it is activated by lipopolysaccharide (LPS) and saturated fatty acids, which are inducers of insulin resistance, TLR4 may be a candidate for participation in the cross-talk between inflammatory and metabolic signals. Here, we show that C3H/HeJ mice, which have a loss-of-function mutation in TLR4, are protected against the development of diet-induced obesity. In addition, these mice demonstrate decreased adiposity, increased oxygen consumption, a decreased respiratory exchange ratio, improved insulin sensitivity and enhanced insulin signaling capacity in adipose tissue, muscle and liver, as compared to control mice during high fat feeding. Moreover, in these tissues, control mice fed on a high fat diet show an increase in IKKß and JNK activity, which is prevented in C3H/HeJ mice. In isolated muscles from C3H/HeJ a protection from saturated fatty acid-induced insulin resistance is observed. Thus, TLR4 appears to be an important mediator of obesity and insulin resistance and a potential target for the therapy of these highly prevalent medical conditionsDoutoradoCiencia BasicaDoutor em Clínica Médic

Translational research into gut microbiota: new horizons on obesity treatment: updated 2014

Obesity is currently a pandemic of worldwide proportions affecting millions of people. Recent studies have proposed the hypothesis that mechanisms not directly related to the human genome could be involved in the genesis of obesity, due to the fact that, when a population undergoes the same nutritional stress, not all individuals present weight gain related to the diet or become hyperglycemic. The human intestine is colonized by millions of bacteria which form the intestinal flora, known as gut flora. Studies show that lean and overweight human may present a difference in the composition of their intestinal flora; these studies suggest that the intestinal flora could be involved in the development of obesity. Several mechanisms explain the correlation between intestinal flora and obesity. The intestinal flora would increase the energetic extraction of non-digestible polysaccharides. In addition, the lipopolysaccharide from intestinal flora bacteria could trigger a chronic sub-clinical inflammatory process, leading to obesity and diabetes. Another mechanism through which the intestinal flora could lead to obesity would be through the regulation of genes of the host involved in energy storage and expenditure. In the past five years data coming from different sources established causal effects between intestinal microbiota and obesity/insulin resistance, and it is clear that this area will open new avenues of therapeutic to obesity, insulin resistance and DM2.Obesity is currently a pandemic of worldwide proportions affecting millions of people. Recent studies have proposed the hypothesis that mechanisms not directly related to the human genome could be involved in the genesis of obesity, due to the fact that, when a population undergoes the same nutritional stress, not all individuals present weight gain related to the diet or become hyperglycemic. The human intestine is colonized by millions of bacteria which form the intestinal flora, known as gut flora. Studies show that lean and overweight human may present a difference in the composition of their intestinal flora; these studies suggest that the intestinal flora could be involved in the development of obesity. Several mechanisms explain the correlation between intestinal flora and obesity. The intestinal flora would increase the energetic extraction of non-digestible polysaccharides. In addition, the lipopolysaccharide from intestinal flora bacteria could trigger a chronic sub-clinical inflammatory process, leading to obesity and diabetes. Another mechanism through which the intestinal flora could lead to obesity would be through the regulation of genes of the host involved in energy storage and expenditure. In the past five years data coming from different sources established causal effects between intestinal microbiota and obesity/insulin resistance, and it is clear that this area will open new avenues of therapeutic to obesity, insulin resistance and DM259215416

Blockade of the CXCR3/CXCL10 axis ameliorates inflammation caused by immunoproteasome dysfunction

Immunoproteasomes regulate the degradation of ubiquitin-coupled proteins and generate peptides that are preferentially presented by MHC class I. Mutations in immunoproteasome subunits lead to immunoproteasome dysfunction, which causes proteasome-associated autoinflammatory syndromes (PRAAS) characterized by nodular erythema and partial lipodystrophy. It remains unclear, however, how immunoproteasome dysfunction leads to inflammatory symptoms. Here, we established mice harboring a mutation in Psmb8 (Psmb8-KI mice) and addressed this question. Psmb8-KI mice showed higher susceptibility to imiquimod-induced skin inflammation (IMS). Blockade of IL-6 or TNF-α partially suppressed IMS in both control and Psmb8-KI mice, but there was still more residual inflammation in the Psmb8-KI mice than in the control mice. DNA microarray analysis showed that treatment of J774 cells with proteasome inhibitors increased the expression of the Cxcl9 and Cxcl10 genes. Deficiency in Cxcr3, the gene encoding the receptor of CXCL9 and CXCL10, in control mice did not change IMS susceptibility, while deficiency in Cxcr3 in Psmb8-KI mice ameliorated IMS. Taken together, these findings demonstrate that this mutation in Psmb8 leads to hyperactivation of the CXCR3 pathway, which is responsible for the increased susceptibility of Psmb8-KI mice to IMS. These data suggest the CXCR3/CXCL10 axis as a new molecular target for treating PRAAS

Translational research into gut microbiota:new horizons on obesity treatment: updated 2014

Obesity is currently a pandemic of worldwide proportions affecting millions of people. Recent studies have proposed the hypothesis that mechanisms not directly related to the human genome could be involved in the genesis of obesity, due to the fact that, when a population undergoes the same nutritional stress, not all individuals present weight gain related to the diet or become hyperglycemic. The human intestine is colonized by millions of bacteria which form the intestinal flora, known as gut flora. Studies show that lean and overweight human may present a difference in the composition of their intestinal flora; these studies suggest that the intestinal flora could be involved in the development of obesity. Several mechanisms explain the correlation between intestinal flora and obesity. The intestinal flora would increase the energetic extraction of non-digestible polysaccharides. In addition, the lipopolysaccharide from intestinal flora bacteria could trigger a chronic sub-clinical inflammatory process, leading to obesity and diabetes. Another mechanism through which the intestinal flora could lead to obesity would be through the regulation of genes of the host involved in energy storage and expenditure. In the past five years data coming from different sources established causal effects between intestinal microbiota and obesity/insulin resistance, and it is clear that this area will open new avenues of therapeutic to obesity, insulin resistance and DM2

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

Markers of Memory CD8

BNT162b2, a nucleoside-modified mRNA vaccine for SARS-CoV-2 spike glycoprotein (S), provides approximately 95% efficacy for preventing COVID-19. However, it remains unclear how effectively memory CD8+ T cells are generated and which genetic and environmental factors affect the generation and function of memory CD8+ T cells elicited by this vaccine. Here, we investigated the frequency and functions of memory CD8+ T cells 3 weeks after the second vaccination in the Japanese population. Using a peptide-MHC pentamer, we detected an increased number of memory CD8+ T cells together with increased serum anti-S protein antibody in females compared with that in males, but the frequency of pentamer-positive cells was not positively correlated with antibody titers. Memory precursor effector cells (KLRG1-CD127+) among both CD8+ cells and pentamer+ cells and effector cells (CD38-HLA-DR+) among pentamer+ cells were more abundant in females than in males. Upon S protein-mediated stimulation of T cells, the intensity of CD107a and granzyme B expression was increased in females compared with that in males, indicating stronger memory CD8+ T cell responses in females than in males. Our studies showed that the BNT162b2 vaccine elicits increased memory CD8+ T cell proliferation and secondary CTL responses in females compared with those in males in the Japanese population. These findings provide an important basis for the distinct sex difference in cellular immune responses to mRNA vaccination and suggest that memory precursor effector cells can be one of markers to evaluate and boost cellular immunity induced by BNT162b2