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Biomedical subjects

Shimon Sakaguchi

Publications and source records attributed to Shimon Sakaguchi.

At least 37 records · Page 2Linked to original sources
PubMed2006

Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease.

Naturally arising CD25+ CD4+ regulatory T (Treg) cells, most of which are produced by the normal thymus as a functionally mature T-cell subpopulation, play key roles in the maintenance of immunologic self-tolerance and negative control of a variety of physiological and pathological immune responses. Natural Tregs specifically express Foxp3, a transcription factor that plays a critical role in their development and function. Complete depletion of Foxp3-expressing natural Tregs, whether they are CD25+ or CD25-, activates even weak or rare self-reactive T-cell clones, inducing severe and widespread autoimmune/inflammatory diseases. Natural Tregs are highly dependent on exogenously provided interleukin (IL)-2 for their survival in the periphery. In addition to Foxp3 and IL-2/IL-2 receptor, deficiency or functional alteration of other molecules, expressed by T cells or non-T cells, may affect the development/function of Tregs or self-reactive T cells, or both, and consequently tip the peripheral balance between the two populations toward autoimmunity. Elucidation of the molecular and cellular basis of this Treg-mediated active maintenance of self-tolerance will facilitate both our understanding of the pathogenetic mechanism of autoimmune disease and the development of novel methods of autoimmune disease prevention and treatment via enhancing and re-establishing Treg-mediated dominant control over self-reactive T cells.

Animals↗
PubMed2006

Glucocorticoid-induced tumour necrosis factor receptor family-related receptor signalling exacerbates hapten-induced colitis by CD4+ T cells.

The glucocorticoid-induced tumour necrosis factor receptor family related gene (GITR) has been reported to be expressed on the activated T and CD4(+)CD25(+) regulatory T cells (Treg). Signalling triggered by GITR not only neutralizes the suppressive effect of Treg cells, but also augments activation, proliferation and cytokine production of effector T cells. To test the role of GITR in 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced colitis - a murine model of mucosal inflammation - TNBS-injected Balb/c mice were treated with agonistic anti-GITR monoclonal antibody (mAb). Anti-GITR treatment increased the death rate compared to rat IgG-treated mice. Typically, death occurred within 4 days after the TNBS injection when the mice were treated with anti-GITR. The mice that survived anti-GITR treatment suffered from severe inflammation in their entire intestines. CD4(+) T-depletion protected the mice from colitis; even an anti-GITR effect was not apparent. In contrast, CD8(+) T depletion showed less protective than did CD4(+) T depletion. Stimulation of GITR enhanced the production of proinflammatory cytokines including interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-12. It also enhanced the humoral response such as serum levels of IgG(2b) and IgA, which was completely dependent on CD4(+) T cells. Taken together, this study demonstrated that GITR signalling on CD4(+) T cells is involved in the development and progress of colitis by enhancing both T helper type 1 (Th1) and Th2 type responses.

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PubMed2006

Delineation of immunoregulatory properties of adult T-cell leukemia cells.

We characterized leukemic cells from 20 adult T-cell leukemia (ATL) cases and 7 ATL-derived cell lines in terms of Foxp3 messenger RNA (mRNA) expression, cytokine production, cell surface markers associated with regulatory T-cells (Treg), and in vitro immunoregulatory activity and compared the results with those of cells from 3 T-cell-type chronic lymphocytic leukemia (T-CLL) patients and normal CD4+ T-cells. Real-time polymerase chain reaction analysis showed that cells from 10 ATL cases, 1 T-CLL case, and 1 ATL cell line had higher Foxp3 mRNA levels than CD4+ T-cells. In 5 ATL cases, Foxp3 levels were comparable to those of CD4+CD25+ T-cells. Flow cytometric analysis revealed that CTLA-4 expression correlated with Foxp3 mRNA level in ATL cells. The cells of all ATL cases examined produced no interleukin 2 or interferon gamma after iono-mycin and phorbolmyristate acetate stimulation. Cases with low Foxp3 expression (Foxp3-low) tended to express higher levels of transforming growth factor beta mRNA, but this trend was not statistically significant. An in vitro inhibition assay showed that the proliferation of normal CD4+CD25- T-cells stimulated with anti-CD3 monoclonal antibody and autologous dendritic cells was significantly suppressed by coculture with Foxp3-high ATL cells. These results indicate that Foxp3 expression is variable in ATL cases and that Foxp3-high ATL cells, which resemble Treg phenotypically as well as functionally, may be involved in immune suppression in ATL.

Aged↗
PubMed2005

Animal models of arthritis caused by systemic alteration of the immune system.

Animal models are instrumental in understanding the etiology and pathogenetic mechanisms of rheumatoid arthritis. Several new mouse models have either been produced, including transgenics, gene-knockouts, and gene knock-ins, or established as a spontaneous disease due to natural gene mutations. These models are suitable for addressing the roles of T cells, autoantibodies, cytokines and innate immunity in the development and progression of rheumatoid arthritis. In particular, they now provide insights into how systemic alterations of the immune system result in a local development of chronic arthritis that leads to joint destruction.

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PubMed2005

CD4+ regulatory cells as a potential immunotherapy.

CD4(+) regulatory T (T(R)) cells represent a unique lineage of thymically generated lymphocytes capable of powerfully suppressing immune responses. A large body of experimental data has now confirmed the key role played by these cells in the maintenance of self-tolerance. Increasingly, the importance of these cells is also being recognized in a host of other clinically relevant areas such as transplantation, tumour immunity, allergy and microbial immunity. Additionally, it is also possible to generate T(R) cells by using a variety of ex vivo experimental approaches. We will focus here on harnessing the suppressive abilities of both these families of regulatory cells and how this should give us access to a potent cell-based immunotherapy appropriate for clinical application.

Forkhead Transcription Factors↗
PubMed2005

Treatment of advanced tumors with agonistic anti-GITR mAb and its effects on tumor-infiltrating Foxp3+CD25+CD4+ regulatory T cells.

T cell stimulation via glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) can evoke effective tumor immunity. A single administration of agonistic anti-GITR monoclonal antibody (mAb) to tumor-bearing mice intravenously or directly into tumors provoked potent tumor-specific immunity and eradicated established tumors without eliciting overt autoimmune disease. A large number of CD4+ and CD8+ T cells, including interferon (IFN)-gamma-secreting cells, infiltrated regressing tumors. Tumor-specific IFN-gamma-secreting CD4+ and CD8+ T cells also increased in the spleen. The treatment led to tumor rejection in IFN-gamma-intact mice but not IFN-gamma-deficient mice. Furthermore, coadministration of anti-GITR and anti-CTLA-4 mAbs had a synergistic effect, leading to eradication of more advanced tumors. In contrast, coadministration of anti-CD25 and anti-GITR mAbs was less effective than anti-GITR treatment alone, because anti-CD25 depleted both CD25+-activated effector T cells and CD25+CD4+ naturally occurring regulatory T (T reg) cells. Importantly, CD4+ T cells expressing the T reg-specific transcription factor Foxp3 predominantly infiltrated growing tumors in control mice, indicating that tumor-infiltrating natural Foxp3+CD25+CD4+ T reg cells may hamper the development of effective tumor immunity. Taken together, T cell stimulation through GITR attenuates T reg-mediated suppression or enhances tumor-killing by CD4+ and CD8+ effector T cells, including those secreting IFN-gamma, or both. Agonistic anti-GITR mAb is therefore instrumental in treating advanced cancers.

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PubMed2005

Analysis of the underlying cellular mechanisms of anti-CD154-induced graft tolerance: the interplay of clonal anergy and immune regulation.

Although it has been shown that CD4(+)CD25(+) regulatory T cells (T(reg)) contribute to long-term graft acceptance, their impact on the effector compartment and the mechanism by which they exert suppression in vivo remain unresolved. Using a CD4(+) TCR transgenic model for graft tolerance, we have unveiled the independent contributions of anergy and active suppression to the fate of immune and tolerant alloreactive T cells in vivo. First, it is shown that anti-CD154-induced tolerance resulted in the abortive expansion of the alloreactive, effector T cell pool. Second, commensurate with reduced expansion, there was a loss of cytokine production, activation marker expression, and absence of memory T cell markers. All these parameters defined the tolerant alloreactive T cells and correlated with the inability to mediate graft rejection. Third, the tolerant alloreactive T cell phenotype that is induced by CD154 was reversed by the in vivo depletion of T(reg). Reversal of the tolerant phenotype was followed by rapid rejection of the allograft. Fourth, in addition to T(reg) depletion, costimulation of the tolerant alloreactive T cells or activation of the APC compartment also reverted alloreactive T cell tolerance and restored an activated phenotype. Finally, it is shown that the suppression is long-lived, and in the absence of anti-CD154 and donor-specific transfusion, these T(reg) can chronically suppress effector cell responses, allowing long-lived graft acceptance.

Amino Acid Sequence↗
PubMed2005

Regulatory T cells, derived from naïve CD4+CD25- T cells by in vitro Foxp3 gene transfer, can induce transplantation tolerance.

BACKGROUND: Regulatory T (Treg) cells, generated in vitro by Foxp3 gene transfer into naive CD4+25- T cells, have been shown to inhibit the development of inflammation and autoimmune disease, but it is not known whether they are able to prevent allograft rejection. This study investigated whether Treg cells generated from naive CD4+ T cells by Foxp3 gene transfer could induce transplantation tolerance. METHODS: HY-specific, T-cell receptor (TCR)-transgenic CD4+25- T cells were retrovirally transduced with the Foxp3 gene. The phenotype, function, and cytokine profiles of the transduced cells were examined in vitro by fluorescence-activated cell sorter, T-cell proliferation assays, enzyme-linked immunosorbent assay, and intracellular cytokine staining. Adoptive transfer and skin grafting experiments were conducted to assess whether Foxp3-transduced HY-specific T cells could prevent the rejection of syngeneic male grafts. RESULTS: CD4+25- T cells retrovirally transduced with Foxp3 express a panel of cell surface and intracellular molecules closely associated with Treg activity. This Treg phenotype was stable during in vitro culture with some further maturation. In vitro, Foxp3-transduced cells were functionally anergic and suppressive T cells. In vivo adoptive transfer of Foxp3-transduced HY-specific TCR-transgenic CD4+ T cells protected male skin grafts from rejection by syngeneic females. Retroviral transduction of the Foxp3 gene into non-TCR-transgenic CD4+25- T cells, however, had no influence on male skin graft rejection. CONCLUSION: This study provides the first evidence that Foxp3-transduced T cells can control the rejection of an allogeneic transplant and suggests that T-cell Foxp3 gene transfer may have therapeutic value in clinical transplantation.

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PubMed2005

A role for fungal {beta}-glucans and their receptor Dectin-1 in the induction of autoimmune arthritis in genetically susceptible mice.

A combination of genetic and environmental factors can cause autoimmune disease in animals. SKG mice, which are genetically prone to develop autoimmune arthritis, fail to develop the disease under a microbially clean condition, despite active thymic production of arthritogenic autoimmune T cells and their persistence in the periphery. However, in the clean environment, a single intraperitoneal injection of zymosan, a crude fungal beta-glucan, or purified beta-glucans such as curdlan and laminarin can trigger severe chronic arthritis in SKG mice, but only transient arthritis in normal mice. Blockade of Dectin-1, a major beta-glucan receptor, can prevent SKG arthritis triggered by beta-glucans, which strongly activate dendritic cells in vitro in a Dectin-1-dependent but Toll-like receptor-independent manner. Furthermore, antibiotic treatment against fungi can prevent SKG arthritis in an arthritis-prone microbial environment. Multiple injections of polyinosinic-polycytidylic acid double-stranded RNA also elicit mild arthritis in SKG mice. Thus, specific microbes, including fungi and viruses, may evoke autoimmune arthritis such as rheumatoid arthritis by stimulating innate immunity in individuals who harbor potentially arthritogenic autoimmune T cells as a result of genetic anomalies or variations.

Animals↗
PubMed2005

Definition of target antigens for naturally occurring CD4(+) CD25(+) regulatory T cells.

The antigenic targets recognized by naturally occurring CD4(+) CD25(+) regulatory T cells (T reg cells) have been elusive. We have serologically defined a series of broadly expressed self-antigens derived from chemically induced mouse sarcomas by serological identification of antigens by recombinant expression cloning (SEREX). CD4(+) CD25(+) T cells from mice immunized with SEREX-defined self-antigens had strong suppressive activity on peptide-specific proliferation of CD4(+) CD25(-) T cells and CD8(+) T cells. The suppressive effect was observed without in vitro T cell stimulation. Foxp3 expression in these CD4(+) CD25(+) T cells from immunized mice was 5-10 times greater than CD4(+) CD25(+) T cells derived from naive mice. The suppressive effect required cellular contact and was blocked by anti-glucocorticoid-induced tumor necrosis factor receptor family-related gene antibody. In vitro suppressive activity essentially disappeared 8 wk after the last immunization. However, it was regained by in vitro restimulation with cognate self-antigen protein but not with control protein. We propose that SEREX-defined self-antigens such as those used in this study represent self-antigens that elicit naturally occurring CD4(+) CD25(+) T reg cells.

Animals↗
PubMed2005

Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization.

Interleukin (IL)-2 plays a crucial role in the maintenance of natural immunologic self-tolerance. Neutralization of circulating IL-2 by anti-IL-2 monoclonal antibody for a limited period elicits autoimmune gastritis in BALB/c mice. Similar treatment of diabetes-prone nonobese diabetic mice triggers early onset of diabetes and produces a wide spectrum of T cell-mediated autoimmune diseases, including gastritis, thyroiditis, sialadenitis, and notably, severe neuropathy. Such treatment selectively reduces the number of Foxp3-expressing CD25(+) CD4(+) T cells, but not CD25(-) CD4(+) T cells, in the thymus and periphery of normal and thymectomized mice. IL-2 neutralization inhibits physiological proliferation of peripheral CD25(+) CD4(+) T cells that are presumably responding to normal self-antigens, whereas it is unable to inhibit their lymphopenia-induced homeostatic expansion in a T cell-deficient environment. In normal naive mice, CD25(low) CD4(+) nonregulatory T cells actively transcribe the IL-2 gene and secrete IL-2 protein in the physiological state. IL-2 is thus indispensable for the peripheral maintenance of natural CD25(+) CD4(+) regulatory T cells (T reg cells). The principal physiological source of IL-2 for the maintenance of T reg cells appears to be other T cells, especially CD25(low) CD4(+) activated T cells, which include self-reactive T cells. Furthermore, impairment of this negative feedback loop via IL-2 can be a cause and a predisposing factor for autoimmune disease.

Animals↗
PubMed2005

Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism.

CD4+CD25+ regulatory T cells (Treg) are potent immunosuppressive cells that are pivotal in the regulation of peripheral tolerance. In this report, we identify granzyme B (GZ-B) as one of the key components of Treg-mediated suppression. Induction of regulatory activity is correlated with the up-regulation of GZ-B expression. Proof of a functional involvement of GZ-B in contact-mediated suppression by Treg is shown by the reduced ability of Treg from GZ-B-/- mice to suppress as efficiently as Treg from WT mice. GZ-B-mediated suppression is perforin independent, because suppression by Treg from perforin-/- and WT is indistinguishable. Additionally, suppression mediated by Treg appears to be mediated, in part, by the induction of apoptosis in the CD4+CD25- effector cell. In summary, GZ-B is one of the key mechanisms through which CD4+CD25+ Treg induce cell contact-mediated suppression.

Animals↗
PubMed2005

Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice.

Autoimmune regulator (AIRE) gene mutation is responsible for the development of organ-specific autoimmune disease with monogenic autosomal recessive inheritance. Although Aire has been considered to regulate the elimination of autoreactive T cells through transcriptional control of tissue-specific Ags in thymic epithelial cells, other mechanisms of AIRE-dependent tolerance remain to be investigated. We have established Aire-deficient mice and examined the mechanisms underlying the breakdown of self-tolerance. The production and/or function of immunoregulatory T cells were retained in the Aire-deficient mice. The mice developed Sjogren's syndrome-like pathologic changes in the exocrine organs, and this was associated with autoimmunity against a ubiquitous protein, alpha-fodrin. Remarkably, transcriptional expression of alpha-fodrin was retained in the Aire-deficient thymus. These results suggest that Aire regulates the survival of autoreactive T cells beyond transcriptional control of self-protein expression in the thymus, at least against this ubiquitous protein. Rather, Aire may regulate the processing and/or presentation of self-proteins so that the maturing T cells can recognize the self-Ags in a form capable of efficiently triggering autoreactive T cells. With the use of inbred Aire-deficient mouse strains, we also demonstrate the presence of some additional factor(s) that determine the target-organ specificity of the autoimmune disease caused by Aire deficiency.

Animals↗
PubMed2005

Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self.

Naturally arising CD25(+)CD4(+) regulatory T cells actively maintain immunological self-tolerance. Deficiency in or dysfunction of these cells can be a cause of autoimmune disease. A reduction in their number or function can also elicit tumor immunity, whereas their antigen-specific population expansion can establish transplantation tolerance. They are therefore a good target for designing ways to induce or abrogate immunological tolerance to self and non-self antigens.

Animals↗
PubMed2005

[Regulatory T cell and autoimmune diseases].

CD25+CD4+ regulatory T cells are naturally anergic and suppressive. They differentiate through thymus as professional regulator to control immunological self-tolerance in the periphery. When they are depleted from normal animals, various organ-specific autoimmune diseases spontaneously develop, and reconstitution of regulatory T cells prevents the diseases. Transcriptional factor FoxP3 is the master gene for differentiation and function of regulatory T cells. Mutation of FoxP3 gene causes development of autoimmune disease in both human and mouse. There are accumulating reports that regulatory T cells are abnormal in their number or function in several animal models and also patients with autoimmune diseases. These findings indicate that regulatory T cells are involved in the pathogenesis of many autoimmune diseases. Regulatory T cells can also be employed for the treatment of autoimmune diseases. Further studies of regulatory T cells, especially the detection of their specific markers and the development of the method to propagate them in an antigen-specific manner, will facilitate their clinical application.

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