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Koji Yasutomo

Publications and source records attributed to Koji Yasutomo.

At least 19 recordsLinked to original sources
PubMed2006

Lunatic fringe controls T cell differentiation through modulating notch signaling.

T cells differentiate from bone marrow-derived stem cells by expressing developmental stage-specific genes. We here searched arrays of genes that are highly expressed in mature CD4-CD8+ (CD8 single-positive (SP)) T cells but little in CD4+CD8+ (double-positive (DP)) cells by cDNA subtraction. Lunatic fringe (Lfng), a modulator of Notch signaling, was identified to be little expressed in DP cells and highly expressed in CD8SP T cell as well as in CD4-CD8- (double-negative (DN)) and mature CD4+CD8- (CD4SP) T cells. Thus, we examined whether such change of expression of Lfng plays a role in T cell development. We found that overexpression of Lfng in Jurkat T cells strengthened Notch signaling by reporter gene assay, indicating that Lfng is a positive regulator for Notch signaling in T cells. The enforced expression of Lfng in thymocytes enhanced the development of immature CD8SP cells but decreased mature CD4SP and CD8SP cells. In contrast, the down-regulation of Lfng in thymocytes suppressed DP cells development due to the defective transition from CD44+CD25- stage to subsequent stage in DN cells. The overexpression of Lfng in fetal liver-derived hemopoietic stem cells enhanced T cell development, whereas its down-regulation suppressed it. These results suggested that the physiological high expression of Lfng in DN cells contributes to enhance T cell differentiation through strengthening Notch signaling. Shutting down the expression of Lfng in DP cells may have a physiological role in promoting DP cells differentiation toward mature SP cells.

Animals↗
PubMed2006

Clinical roles of increased populations of Foxp3+CD4+ T cells in peripheral blood from advanced pancreatic cancer patients.

OBJECTIVES: Further metastasis should be avoided in pancreatic cancer (PC) patients for effective surgical treatment. Regulatory T cells (Foxp3CD4 T cells including CD4CD25 T cells and CD4CD25 T cells) play important roles in tumor immunity. This study aimed to investigate whether regulatory T cells participate in metastasis. METHODS: Peripheral blood was withdrawn from PC patients, as well as healthy volunteer donors as controls. The peripheral blood mononuclear cells (PBMCs) were subjected to FACScan analysis after labeling with anti-CD4, anti-CD25, and anti-Foxp3 antibodies. Tumor markers, including DUPAN2 and CA19-9, surface markers, such as the CD4/CD8 ratio, and the CD57 cell population were assessed. Clinical stages were classified according to the TNM classification. RESULTS: The Foxp3CD4 T-cell population among the PBMCs was significantly increased in PC patients (8.10% +/- 4.65%) compared with healthy donors (2.47 +/- 0.78%) (P < 0.001). No significant relationships existed for the tumor markers, CD4/CD8 ratio, and CD57 cells. However, a significant correlation was found between Foxp3CD4 T cells among the PBMCs and the TNM stage (P < 0.05). CONCLUSIONS: Foxp3CD4 T cells are good markers for metastasis detection in PC patients and more accurate than other conventional tumor markers, especially at advanced stages of the disease.

Aged↗
PubMed2005

Resistance of regulatory T cells to glucocorticoid-induced [corrected] TNFR family-related protein (GITR) during Plasmodium yoelii infection.

CD4+ T cells are the major effector T cells against blood-stage Plasmodium yoelii infection. On the other hand, the lethal strain of P. yoelii (PyL) has acquired an escape mechanism from host T cell immunity by activating CD4+CD25+ regulatory T cells (Treg). Although the activation of Treg during PyL infection precludes the clearance of PyL from mice, it remains unclear whether activation of Treg is attributable to a specific response against PyL infection. Thus, we examined here whether Treg proliferate in an antigen-dependent manner during PyL infection. We also investigated the effector and regulatory mechanisms of Treg. Infection with PyL increased the number of CD4+CD25+ T cells, in which expression of Foxp3 mRNA is up-regulated. The Treg that were transferred into mice infected with PyL, but not with a non-lethal strain of P. yoelii (PyNL), proliferated during the initial 5 days following infection. The Treg from PyL-infected mice showed strong suppression compared with those from naive or PyNL-infected mice, and could suppress T cell activation by recognizing PyL- but not PyNL-derived antigens. Furthermore, the suppressive function of Treg activated in PyL-infected but not in naive mice could not be inhibited by treatment with an anti-glucocorticoid-induced TNFR family-related protein (GITR) mAb. These findings indicate that PyL infection specifically activates Treg that are specific for PyL-derived antigens. The infection also induces resistance for Treg to GITR signaling, and this eventually contributes to the escape of parasites from host T cell immunity.

Animals↗
PubMed2005

Malaria: immune evasion by parasites.

Malaria is one of the most life-threatening infectious diseases worldwide. Specific immunity to natural infection is acquired slowly despite a high degree of repeated exposure and rarely continues for a long time even in endemic areas. Malaria parasites have evolved to acquire diverse immune evasion mechanisms that evoke poor immune responses and allow infection of individuals previously exposed. The shrewd schema of malaria parasites also hampers the development of effective vaccines. Furthermore, some of those mechanisms are essential for malaria pathogenesis. In this article, an outline of protective immunity to malaria is given, then strategies used by malaria parasites to evade host immunity, including antigen diversity/polymorphism, antigen variation and total immune suppression, are reviewed. Finally, trials to control malaria based on accumulating insights into the host-parasite relationship are discussed.

Animals↗
PubMed2005

Regulation of acquired immune system by notch signaling.

T- and B-cells are generated from hematopoietic stem cells through lymphoid intermediates. The interplay of intrinsic and extrinsic signals determines cell fate at the branch point for T- and B-cell lineages and at the post-commitment stage of lymphogenesis. The mature lymphocytes differentiate into effector/memory cells by antigen recognition, and those differentiation steps are also governed by a series of cell fate choices and survival signals, which allows cells to acquire distinct effector functions. The identification of the molecular details that dictate lymphocyte development and differentiation will improve understanding of acquired immune responses. Recent studies have revealed that Notch molecules, evolutionarily conserved transmembrane receptors, play key roles in lymphocyte development and differentiation. In this article, we review recent knowledge regarding the roles of Notch signaling in controlling both lymphocyte development and acquisition of effector functions.

Animals↗
PubMed2005

Antigen-driven T-cell repertoire selection.

The immune system has evolved to combat infectious organisms through the coordination of both innate and acquired immune responses. Innate immune responses generally pass their roles in eradicating pathogens to acquired immune responses conducted by T and B cells. T and B cells generate diverse antigen-specific receptors through gene recombination, and both cell repertoires are shaped during their development by recognizing self-antigens. After cell maturation, the repertoire selection is further developed by recognizing non-self-antigens, which is essential for efficient eradication of pathogens. Those antigen-driven selections are seen not only in conventional CD4(+) and CD8(+) T cells but also in CD4(+)CD25(+) regulatory T cells. In this article, we review current concepts of repertoire selection of conventional T cells, as well as regulatory T cells, and discuss the physiological role of such selection in controlling acquired immune responses against pathogens.

Animals↗
PubMed2004

Notch governing mature T cell differentiation.

The differentiation of naive T cells to effector/memory T cells is regulated by a variety of factors. The recent advance of the contribution of Notch signaling in this differentiation step has provided a new path to better understand the acquisition or persistence of effector function of mature T cells. In this review, we summarize emerging and, in some points, conflicting evidence for Notch signaling on mature T cell activation and differentiation.

Animals↗
PubMed2004

Antigen-specific T cell repertoire modification of CD4+CD25+ regulatory T cells.

T cell immune responses are regulated by the interplay between effector and suppressor T cells. Immunization with Ag leads to the selective expansion and survival of effector CD4(+) T cells with high affinity TCR against the Ag and MHC. However, it is not known if CD4(+)CD25(+) regulatory T cells (T(reg)) recognize the same Ag as effector T cells or whether Ag-specific TCR repertoire modification occurs in T(reg). In this study, we demonstrate that after a primary Ag challenge, T(reg) proliferate and TCR repertoire modification is observed although both of these responses were lower than those in conventional T cells. The repertoire modification of Ag-specific T(reg) after primary Ag challenge augmented the total suppressive function of T(reg) against TCR repertoire modification but not against the proliferation of memory CD4(+) T cells. These results reveal that T cell repertoire modification against a non-self Ag occurs in T(reg), which would be crucial for limiting excess primary and memory CD4(+) T cell responses. In addition, these studies provide evidence that manipulation of Ag-specific T(reg) is an ideal strategy for the clinical use of T(reg).

Animals↗
PubMed2004

Transforming growth factor-beta in renal disease with glycogen storage disease I.

We report a 14-year-old patient with Japanese glycogen storage disease I (GSD-I) who was found to have proteinuria. Renal biopsy revealed massive tubular atrophy and interstitial fibrosis with mononuclear cell infiltration, but the glomeruli were almost normal. The epithelial cells of tubules contained periodic acid-Schiff-positive glycogen deposits digested by diastase. In an immunohistological study, transforming growth factor (TGF)-beta expression was increased in tubular epithelial cells compared with a normal control kidney specimen. These data suggest that increased TGF-beta expression is involved in the pathophysiology of renal interstitial fibrosis in a patient with GSD-I.

Adolescent↗
PubMed2004

Sisters with alpha-mannosidosis and systemic lupus erythematosus.

UNLABELLED: Alpha-mannosidosis is an autosomal recessive disorder caused by deficiency of lysosomal alpha-mannosidase (LAMAN). Here, we report two sisters with alpha-mannosidosis who developed systemic lupus erythematosus (SLE). The sisters were both homozygous for a one bp deletion within the LAMAN gene resulting in a truncated gene product. The coincidence of alpha-mannosidosis and SLE are discussed with regard to both clinical and molecular findings. CONCLUSION: alpha-mannnosidosis may contribute to the onset of systemic lupus erythematosus in predisposed patients.

Adult↗
PubMed2004

Effective treatment of a mouse model of Sjögren's syndrome with eyedrop administration of anti-CD4 monoclonal antibody.

OBJECTIVE: To determine whether eyedrop administration of an anti-CD4 monoclonal antibody (mAb) is effective in the treatment of Sjögren's syndrome (SS) using a mouse model of the disease. METHODS: The anti-CD4 mAb was administered daily into the eyes of mice with SS from ages 4 to 8 weeks or ages 10 to 12 weeks. During treatment, tear volume was monitored and after final treatment, histologic features of the lacrimal and salivary glands, the phenotypes and function of T cells, and serum titers of anti-alpha-fodrin antibody were examined. RESULTS: Eyedrop administration of anti-CD4 mAb before the onset of SS prevented the autoimmune pathology seen in the lacrimal glands but not that in the salivary glands. Furthermore, eyedrop administration of anti-CD4 mAb after the development of SS inhibited mononuclear cell infiltration and the destruction of parenchyma only in the lacrimal glands. Eyedrop administration of anti-CD4 mAb suppressed the local activation of CD4+ T cells rather than deleting CD4+ T cells, which reduced the expansion of pathologic CD4+ T cells against alpha-fodrin. CONCLUSION: These results demonstrate the remarkable efficacy of anti-CD4 mAb eyedrops in the treatment of SS eye symptoms, which illustrates a new antibody-based therapeutic strategy for patients with eye problems caused by SS as well as other diseases.

Administration, Topical↗
PubMed2004

DNaseI in pathogenesis of systemic lupus erythematosus.

The aberrant activation of lymphocytes causes autoimmune diseases. Although there are many candidate molecules that are involved in the pathogenesis of autoimmune diseases, it still remains unclear how immunological tolerance is disturbed in each autoimmune disease. Recently, we discovered two patients suffering from systemic lupus erythematosus (SLE) with a defect in the DNaseI gene locus. According to immunological and genetic analysis, we hypothesize that defective antigen clearance, especially accumulation of nucleosomal antigens, is responsible for the development of SLE. In this article, we review the pathogenesis of SLE from the view of defective self-antigen clearance due to low DNaseI activity.

Deoxyribonuclease I↗
PubMed2004

Donor-specific tolerance induced by simultaneous allogeneic islet transplantation with CD4+CD25+ T-cells into hepatic parenchyma in mice.

BACKGROUND: The allogeneic islets transplantation is an ideal therapeutic strategy for patients with diabetes mellitus. However, it has been difficult to induce immunological tolerance against islets grafts. The CD4+CD25+ regulatory T-cells (Treg) play a role in suppressing T-cell activation. Thus, we evaluated whether Treg can regulate donor-specific T-cell tolerance that received allogeneic islets into the hepatic parenchyma (ITxHP) along with Treg. METHODS: C3H/He mice were used as donors; and streptozotocin-induced diabetic BALB/c mice were recipients. The protocol included three groups: Group A recipients received only 300 IE islets; Group B was given 300 IE islets and whole splenocytes; Group C was given 300 IE islets and Treg purified from peripheral lymph nodes. RESULTS: For all mice in Groups A and B, the fasting blood sugar exceeded 250mg/dl and graft rejection was observed. GVHD was observed earlier in Group B than in Group A. In contrast graft survival exceeded 30 days for two mice in Group C (50%, mean POD 28.5 +/- 24.0, P<0.05). Mixed lymphocyte reaction showed that T-cells from tolerant mice had very weak responses against spleen cells from C3H mice. CONCLUSIONS: The simultaneous ITxHP with CD4+CD25+ T-cells administration prolonged islet graft survivals and induced donor-specific hyporesponsiveness.

Animals↗
PubMed2003

Escape of malaria parasites from host immunity requires CD4+ CD25+ regulatory T cells.

Infection with malaria parasites frequently induces total immune suppression, which makes it difficult for the host to maintain long-lasting immunity. Here we show that depletion of CD4(+)CD25(+) regulatory T cells (T(reg)) protects mice from death when infected with a lethal strain of Plasmodium yoelii, and that this protection is associated with an increased T-cell responsiveness against parasite-derived antigens. These results suggest that activation of T(reg) cells contributes to immune suppression during malaria infection, and helps malaria parasites to escape from host immune responses.

Animals↗
PubMed2003

Breakdown of peripheral T-cell tolerance by chronic interleukin-15 elevation.

Thymic deletion purges the repertoire of most developing T cells with the potential for overt self-reactivity, but some self-specific cells do emerge into the peripheral pool. Under most conditions, these potentially autoaggressive cells remain in a quiescent state. However, in some circumstances, they become activated and acquire effector function, leading to immune disease. It is thus important to clarify the mechanism(s) responsible for determining the balance between such inappropriate T-cell activation and the normal state of peripheral tolerance. In this article, we show that chronic elevation of interleukin-15 levels interferes with the tolerant state of CD8+ T cells through a process that involves activation of nonlymphoid antigen-presenting cells by CD4+asialo-GM1+ (ASGM1) or both CD4+ASGM1- and CD4-ASGM1+ cells. These findings suggest a potential role for dysregulated interleukin-15 production in promoting tolerance breakdown. This new information may be of potential use in improving tumor vaccines to self-antigens and in ameliorating autoimmune or graft-versus-host disease.

Animals↗
PubMed2003

Delta1-Notch3 interactions bias the functional differentiation of activated CD4+ T cells.

Following activation by antigen, naive CD4+ T helper precursor cells execute distinct genetic programs that result in their differentiation toward the type 1 or type 2 helper T cell (Th1 or Th2) phenotype. Although the differentiation and function of these Th subsets has been well studied, little is known about the contribution to these differentiation events of cell surface receptors other than those for soluble cytokines, such as IL-12 or IL-4. Here, we provide direct evidence that the Delta1 interaction with Notch3 on CD4+ T cells transduces signals, promoting development toward the Th1 phenotype. The positive role of Notch signaling in effector cell differentiation was dose dependent, with high levels of stimulation resulting in reduced T cell activation. Our data revealed a clear contribution of Notch pathways to Th1 versus Th2 fate decisions, while also providing insight into another mechanism for inhibition of CD4+ T cell activation.

Animals↗
PubMed2002

The cellular and molecular mechanism of CD4/CD8 lineage commitment.

A unique feature of alpha beta T-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.

Animals↗