Motoko Kotani

Tokyo University of Science, Edo, Tōkyō, Japan

Are you Motoko Kotani?

Claim your profile

Publications (9)52.91 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: In order to fully understand T cell-mediated immunity, the mechanisms that regulate clonal expansion and cytokine production by CD4(+) antigen-specific effector T cells in response to a wide range of antigenic stimulation needs clarification. For this purpose, panels of antigen-specific CD4(+) T cell clones with different thresholds for antigen-induced proliferation were generated by repeated stimulation with high- or low-dose antigen. Differences in antigen sensitivities did not correlate with expression of TCR, CD4, adhesion or costimulatory molecules. There was no significant difference in antigen-dependent cytokine production by TG40 cells transfected with TCR obtained from either high- or low-dose-responding T cell clones, suggesting that the affinity of TCRs for their ligands is not primary determinant of T cell antigen reactivity. The proliferative responses of all T cell clones to both peptide stimulation and to TCRbeta crosslinking revealed parallel dose-response curves. These results suggest that the TCR signal strength of effector T cells and threshold of antigen reactivity is determined by an intrinsic property, such as the TCR signalosome and/or intracellular signaling machinery. Finally, the antigen responses of high- and low-peptide-responding T cell clones reveal that clonal expansion and cytokine production of effector T cells occur independently of antigen concentration. Based on these results, the mechanisms underlying selection of high "avidity" effector and memory T cells in response to pathogen are discussed.
    Biochemical and Biophysical Research Communications 04/2009; 380(4):742-7. DOI:10.1016/j.bbrc.2009.01.123 · 2.28 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although it is well-known that the ICOS-ICOS ligand (ICOSL) costimulatory pathway is important for many immune responses, recent accumulated evidence suggests that dysregulation of this pathway may lead to and/or exaggerate autoimmune responses. ICOS is induced on the cell surface after T cell activation. Similarly, ICOSL is up-regulated on APCs by several mitogenic stimuli. However, the mechanism regulating expression of the ICOS-ICOSL pair, and the significance of controlling their expression for an appropriate immune response, is largely unknown. To gain a better understanding of the importance of fine control of the ICOS-ICOSL costimulatory pathway, we generated ICOS-transgenic (Tg) mice that have high constitutive expression of ICOS in all T cells. Using ICOS-Tg mice, we studied whether in vivo immune responses were affected. Unexpectedly, we first found that ICOS-Tg mice exhibited a phenotype resembling ICOS-deficient mice in their Ag-specific Ab response, such as a defect in class switch recombination. Further examination revealed that ICOSL expression of APCs was significantly suppressed in ICOS-Tg mice. Interestingly, suppression of ICOSL was induced by interaction of ICOSL with ICOS, and it seemed to be regulated at the posttranscriptional level. The suppressive effect of the ICOS-ICOSL interaction overcame the positive effect of CD40 or B cell activation factor of the TNF family (BAFF) stimulation on ICOSL expression. Together, our studies demonstrate a novel mechanism for the regulation of ICOSL expression in vivo and suggest that the ICOS costimulatory pathway is subject to negative feedback regulation by ICOSL down-regulation in response to ICOS expression.
    The Journal of Immunology 05/2008; 180(8):5222-34. DOI:10.4049/jimmunol.180.8.5222 · 5.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Interleukin-1 receptor antagonist (IL-1Ra)-deficient mice on a BALB/c background spontaneously develop a chronic inflammatory polyarthropathy closely resembling that of rheumatoid arthritis in humans. To elucidate the role of CD28 costimulatory signals in the development of this disease, we studied IL-1Ra/CD28-double-deficient mice. We crossed IL-1Ra-deficient mice with CD28-deficient mice and observed the incidence and severity of arthritis. To investigate functions of IL-1Ra/CD28-double-deficient T cells, cells were stimulated with CD3 monoclonal antibody or allogeneic antigen-presenting cells (APCs) and their proliferative responses and levels of cytokine production were measured. Disease severity was lower in IL-1Ra/CD28-double-deficient mice than in mice that were deficient only in IL-1Ra, although incidence of arthritis was not affected by the presence or absence of CD28. When pathogenic IL-1Ra-KO T cells were transferred into nude mice, severe arthritis developed. Even though T cells from double-deficient mice showed the same diminished proliferative capacity as was seen in T cells from CD28-single-deficient animals, nude mice into which double-deficient T cells were transferred never developed arthritis. These findings indicate that IL-1Ra/CD28-double-deficient T cells can be activated by IL-1Ra-deficient activated APCs, resulting in induction of arthritis; however, these T cells did not induce the disease under normal conditions, because they did not differentiate into effector/memory phenotype.
    Arthritis & Rheumatology 02/2006; 54(2):473-81. DOI:10.1002/art.21769 · 7.87 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Previously, we reported that allogeneic skin grafts were rapidly rejected by CD28 and CD40 ligand double deficient mice mediated by CD8+ T cells. These results indicated that some elements in addition to CD28- and CD40-mediated costimulation provide stimulatory signals for the activation of donor-specific CD8+ T cells. In this report, we investigated the role of inflammation associated with transplantation on costimulation-independent priming of CD8+ T cell during graft rejection. B6 RAG1 KO mice were transplanted with BALB/c-skin and adoptively transferred with syngeneic CD8+ T cells the same day or 50 days after transplantation. When blockade of CD28- and CD40-mediated costimulation failed to prevent acute rejection of freshly transplanted skin grafts, it efficiently delayed rejection of well-healed skin grafts. These results showed that factors associated with transplantation have essential roles in inducing costimulation blockade-resistant allograft rejection. Costimulation blockade failed to prevent acute graft-infiltration of NK cells and increasing expression of intragraft IL-12 and IL-15. These factors may trigger the graft-infiltration and priming of CD8+ T cells to induce costimulation blockade-resistant allograft rejection.
    American Journal of Transplantation 05/2005; 5(4 Pt 1):702-11. DOI:10.1111/j.1600-6143.2005.00768.x · 6.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: IL-1 receptor antagonist-deficient (IL-1Ra(-/-)) mice spontaneously develop autoimmune arthritis. We demonstrate here that T cells are required for the induction of arthritis; T cell-deficient IL-1Ra(-/-) mice did not develop arthritis, and transfer of IL-1Ra(-/-) T cells induced arthritis in nu/nu mice. Development of arthritis was also markedly suppressed by TNF-alpha deficiency. We found that TNF-alpha induced OX40 expression on T cells and blocking the interaction between either CD40 and its ligand or OX40 and its ligand suppressed development of arthritis. These findings suggest that IL-1 receptor antagonist deficiency in T cells disrupts homeostasis of the immune system and that TNF-alpha plays an important role in activating T cells through induction of OX40.
    Journal of Clinical Investigation 01/2005; 114(11):1603-11. DOI:10.1172/JCI20742 · 13.77 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: It has been shown that simultaneous blockade of CD28- and CD40-mediated costimulatory signals significantly prolongs allograft survival. Although these results led to an expectation of the establishment of specific immunotolerant therapy for organ transplantation, it became evident that these treatments rarely resulted in indefinite allograft survival. To uncover the mechanisms underlying these costimulation blockade-resistant allograft rejections, we studied the process of allogenic skin graft rejection in CD28 and CD40 ligand (L) double-deficient (double-knockout [dKO]) mice. Skin grafts from BALB/c or BALB.B mice were transplanted to C57BL/6 background dKO mice. The frequency of CD4+ and CD8+ T cells responding to alloantigens presented by direct or indirect pathways were defined by the use of a cytostaining assay. BALB/c skin grafts were rapidly rejected by dKO mice. This CD28 and CD40L independent allograft rejection was inhibited by the depletion of CD8+ T cells. In vitro studies indicated that CD8+ T cells from BALB/c skin-grafted dKO mice responded to donor antigen presented only by the direct pathway. Unlike major histocompatibility complex (MHC)-mismatched donors, allogenic skin grafts from MHC-matched donors were accepted by dKO mice. In the absence of CD28 and CD40 costimulatory signals, CD8+ T cells recognize MHC antigens by the direct pathway, resulting in the rejection of skin grafts from MHC-mismatched donors. In contrast, MHC-matched and non-MHC-mismatched donor skin grafts indefinitely survive in dKO mice. These results indicated that donor-host MHC matching may still be critical to costimulation blockade therapy for organ transplantation.
    Transplantation 10/2003; 76(5):854-8. DOI:10.1097/01.TP.0000084868.09385.83 · 3.78 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background. It has been shown that simultaneous blockade of CD28- and CD40-mediated costimulatory signals significantly prolongs allograft survival. Although these results led to an expectation of the establishment of specific immunotolerant therapy for organ transplantation, it became evident that these treatments rarely resulted in indefinite allograft survival. To uncover the mechanisms underlying these costimulation blockade-resistant allograft rejections, we studied the process of allogenic skin graft rejection in CD28 and CD40 ligand (L) double-deficient (double-knockout [dKO]) mice. Methods. Skin grafts from BALB/c or BALB.B mice were transplanted to C57BL/6 background dKO mice. The frequency of CD4+ and CD8+ T cells responding to alloantigens presented by direct or indirect pathways were defined by the use of a cytostaining assay. Results. BALB/c skin grafts were rapidly rejected by dKO mice. This CD28 and CD40L independent allograft rejection was inhibited by the depletion of CD8+ T cells. In vitro studies indicated that CD8+ T cells from BALB/c skin-grafted dKO mice responded to donor antigen presented only by the direct pathway. Unlike major histocompatibility complex (MHC)-mismatched donors, allogenic skin grafts from MHC-matched donors were accepted by dKO mice. Conclusion. In the absence of CD28 and CD40 costimulatory signals, CD8+ T cells recognize MHC antigens by the direct pathway, resulting in the rejection of skin grafts from MHC-mismatched donors. In contrast, MHC-matched and non-MHC-mismatched donor skin grafts indefinitely survive in dKO mice. These results indicated that donor-host MHC matching may still be critical to costimulation blockade therapy for organ transplantation. T-cell costimulatory pathways have drawn considerable interest in transplantation as targets for the prevention of allograft rejection (1,2). It was reported that blocking the CD28-B7 costimulatory pathway with the fusion protein cytotoxic T lymphocyte antigen (CTLA) 4-immunoglobulin (Ig) efficiently prevented acute graft rejection in various transplantation models of mice and rats (3,4). Similar studies of the blockade of the CD40-CD40 ligand (L) pathway with monoclonal antibody (mAb) specific for CD40L have been reported (5). Subsequently, a variety of laboratories have studied blocking the CD28-B7 pathway alone, the CD40-CD40L pathway alone, or both the CD40-CD40L and CD28-B7 pathways to interrupt allograft rejection, and reported successful outcomes. Results from these studies were consistent with the idea that blockade of these signal pathways was an effective strategy to prevent acute rejection (6,7). However, even in these transplantation models, costimulation blockade therapy is still unsatisfactory for the prevention of chronic graft rejection (8). On the other hand, the ability of these signal blockade therapies to prevent skin graft rejection remained unclear. Although Larsen et al. first reported that costimulation blockade with anti-CD40L mAb (MR1) and CTLA4-Ig effectively prolonged allo-skin graft survival (6), this effect was shown to be limited to particular strains of recipient mice. In certain strains of mice such as C3H/HeJ, costimulation blockade therapy effectively prolonged allograft survival, whereas other strains including C57BL/6 (B6) showed relative resistance to this therapy (9-11). To apply the costimulation blockade strategy for organ transplantation in clinical settings, mechanisms underlying the costimulation blockade-resistant allograft rejection should be uncovered. For this purpose, we made use of CD28 and CD40L double-deficient (double-knockout [dKO]) mice as transplantation recipients. These mice were particularly suitable for this study because unlike the treatment with costimulation antagonists, their defects in CD28- and CD40-mediated costimulatory signals are specific and complete. In the current study, we demonstrated that dKO mice rejected their grafts from major histocompatibility complex (MHC)-mismatched donors but not MHC-matched and minor antigen-mismatched donors. This graft rejection was mediated by CD8+ T cells that appeared to be primed with donor antigens by direct antigen presentation. These data indicate that even under the extensive blocking of both CD28- and CD40-mediated costimulatory signals, strong immunogenicity of allogenic MHC molecules on graft tissue may activate allospecific CD8+ T cells to become fully capable cytotoxic T cells against allogenic grafts in vivo.
    Transplantation 09/2003; 76(5):854-858. · 3.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Previously, we reported that human T cell leukemia virus type I env-pX region-introduced transgenic (pX-Tg) mice developed an inflammatory polyarthropathy associated with a development of autoimmunity. To elucidate roles of autoimmunity in the development of arthritis, the immune cells were reciprocally replaced between pX-Tg mice and non-transgenic (Tg) mice. When bone marrow (BM) cells and spleen cells from pX-Tg mice were transferred into irradiated non-Tg mice, arthritis developed in these mice. In contrast, arthritis in pX-Tg mice was completely suppressed by non-Tg BM and spleen cells. Similar results were obtained with BM cells only. After the transplantation, T cells, B cells, and macrophages were replaced completely, whereas cells in the joints were replaced partially. In those mice, serum Ig and rheumatoid factor levels correlated with the disease development, and inflammatory cytokine expression was elevated in the arthritic joints. Furthermore, involvement of T cells in the joint lesion was suggested, because the incidence was greatly reduced in athymic nu/nu mice although small proportion of the mice still developed arthritis. These observations suggest that BM stem cells are abnormal, causing autoimmunity in pX-Tg mice, and this autoimmunity plays an important, but not absolute, role in the development of arthritis in this Tg mouse.
    The Journal of Immunology 12/1999; 163(10):5700-7. · 5.36 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We previously reported that transgenic mice carrying the human T cell leukemia virus type I (HTLV-I) env-pX region (pX-transgenic mice) develop rheumatoid-like inflammatory arthropathy, and suggested involvement of autoimmunity in the pathogenicity. In this report, to elucidate pathogenesis of the arthritis, we investigated arthritogenic antigens in the joints. The TCR beta-chain variable region (Vbeta) repertoires in the lymphatic organs were normal in transgenic mice, however, specific Vbeta-positive T cells were expanded oligoclonally in the affected joints, suggesting that specific antigens, but not superantigens, were involved in the expansion of these T cells. These expanded T cells had the same TCR as those of lymph node T cells reactive to type II collagen (IIC). Moreover, these mice were susceptible to IIC-induced arthritis and oligoclonal T cells of the same Vbeta specificity as that found in spontaneously developed arthritic joint accumulated in the arthritic joints after immunization with IIC. These observations show that endogenous IIC is one of the arthritogenic antigens in the joint, suggesting tolerance break to this antigen in pX-transgenic mice.
    European Journal of Immunology 01/1999; 29(1):54-64. DOI:10.1002/(SICI)1521-4141(199901)29:01<54::AID-IMMU54>3.0.CO;2-M · 4.52 Impact Factor

Publication Stats

124 Citations
52.91 Total Impact Points

Institutions

  • 2005–2009
    • Tokyo University of Science
      Edo, Tōkyō, Japan
  • 2003
    • Tokyo Women's Medical University
      Edo, Tōkyō, Japan
  • 1999
    • The University of Tokyo
      • Institute of Medical Science
      Tokyo, Tokyo-to, Japan