The Experts below are selected from a list of 1737423 Experts worldwide ranked by ideXlab platform
Shimon Sakaguchi - One of the best experts on this subject based on the ideXlab platform.
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cd25 cd4 t cells in human cord blood an immunoregulatory subset with naive phenotype and specific expression of forkhead box p3 foxp3 gene
Experimental Hematology, 2004Co-Authors: Yasushi Takahata, Shimon Sakaguchi, Akihiko Nomura, Hidetoshi Takada, Shouichi Ohga, Kenji Furuno, Shunji Hikino, Hideki Nakayama, Toshiro HaraAbstract:Abstract Objective To address the role of cord blood (CB) CD25+CD4+ T cells, the gene expressions and function of this subset were analyzed. Materials and methods CD25+CD4+ T cells fractionated from CB of term and preterm infants were subjected to flow cytometry, quantitative polymerase chain reaction analysis for cytokines, costimulatory molecules, and transcription factors, and functional assays. Results Human preterm CB contained a high proportion of CD25+CD4+ T cells that declined with gestational age to the level of adult peripheral blood (PB). CD25+ or CD25−CD4+ T cells in CB had a higher frequency of CD45RA+ and CD38+ cells than in PB. CB CD25+CD4+ T cells less frequently expressed CD45RO, CD71, and HLA-DR than PB CD25+CD4+ T cells, despite similar expressions on CB and PB CD25−CD4+ T cells. No expression of IL-10, transforming growth factor-β, interleukin-4, and interferon-γ mRNA differed between CB CD25+CD4+ and CD25−CD4+ T cells, in contrast to the high interleukin-10 expression in PB CD25+CD4+ T cells. CTLA-4 was more transcribed in CB and PB CD25+CD4+ T cells than in the counterpart CD25−CD4+ T cells. CD28 or ICOS was similarly expressed in CB and PB T cells. CB CD25+CD4+ T cells effectively suppressed the proliferation of CB CD25−CD4+ T cells in a dose-dependent manner. Human CB and PB CD25+CD4+ T cells preferentially transcribed Foxp3, which governs the regulatory function of this subset in mice. Conclusions These results suggest that CB contains CD25+CD4+ regulatory T cells as a functionally mature population with naive phenotype. This subset may naturally arise and decline in fetus to play a potential immunoregulatory role in intrauterine life.
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immunologic self tolerance maintained by cd25 cd4 regulatory t cells constitutively expressing cytotoxic t lymphocyte associated antigen 4
Journal of Experimental Medicine, 2000Co-Authors: Takeshi Takahashi, Noriko Sakaguchi, Jun Shimizu, Tomoyuki Tagami, Sayuri Yamazaki, Toshimitsu Uede, Tak W Mak, Shimon SakaguchiAbstract:This report shows that cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) plays a key role in T cell–mediated dominant immunologic self-tolerance. In vivo blockade of CTLA-4 for a limited period in normal mice leads to spontaneous development of chronic organ-specific autoimmune diseases, which are immunopathologically similar to human counterparts. In normal naive mice, CTLA-4 is constitutively expressed on CD25+CD4+ T cells, which constitute 5–10% of peripheral CD4+ T cells. When the CD25+CD4+ T cells are stimulated via the T cell receptor in vitro, they potently suppress antigen-specific and polyclonal activation and proliferation of other T cells, including CTLA-4–deficient T cells, and blockade of CTLA-4 abrogates the suppression. CD28-deficient CD25+CD4+ T cells can also suppress normal T cells, indicating that CD28 is dispensable for activation of the regulatory T cells. Thus, the CD25+CD4+ regulatory T cell population engaged in dominant self-tolerance may require CTLA-4 but not CD28 as a costimulatory molecule for its functional activation. Furthermore, interference with this role of CTLA-4 suffices to elicit autoimmune disease in otherwise normal animals, presumably through affecting CD25+CD4+ T cell–mediated control of self-reactive T cells. This unique function of CTLA-4 could be exploited to potentiate T cell–mediated immunoregulation, and thereby to induce immunologic tolerance or to control autoimmunity.
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immunologic self tolerance maintained by cd25 cd4 naturally anergic and suppressive t cells induction of autoimmune disease by breaking their anergic suppressive state
International Immunology, 1998Co-Authors: Takeshi Takahashi, Misako Itoh, Noriko Sakaguchi, Yuhshi Kuniyasu, Masaaki Toda, Makoto Iwata, Jun Shimizu, Shimon SakaguchiAbstract:Elimination of CD25 F T cells, which constitute 5‐10% of peripheral CD4 F T cells in normal naive mice, leads to spontaneous development of various autoimmune diseases. These immunoregulatory CD25 F CD4 F T cells are naturally unresponsive (anergic) in vitro to TCR stimulation, and, upon stimulation, suppress proliferation of CD25 ‐ CD4 F T cells and CD8 F T cells. The antigen concentration required for stimulating CD25 F CD4 F T cells to exert suppression is much lower than that required for stimulating CD25 ‐ CD4 F T cells to proliferate. The suppression, which results in reduced IL-2 production by CD25 ‐ CD4 F T cells, is dependent on cellular interactions on antigen-presenting cells (and not mediated by far-reaching or long-lasting humoral factors or apoptosis-inducing signals) and antigen non-specific in its effector phase. Addition of high doses of IL-2 or anti-CD28 antibody to the in vitro T cell stimulation culture not only breaks the anergic state of CD25 F CD4 F T cells, but also abrogates their suppressive activity simultaneously. Importantly, the anergic/suppressive state of CD25 F CD4 F T cells appeared to be their basal default condition, since removal of IL-2 or anti-CD28 antibody from the culture milieu allows them to revert to the original anergic/suppressive state. Furthermore, transfer of such anergy/suppression-broken T cells from normal mice produces various autoimmune diseases in syngeneic athymic nude mice. These results taken together indicate that one aspect of immunologic self-tolerance is maintained by this unique CD25 F CD4 F naturally anergic/
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Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state.
International Immunology, 1998Co-Authors: Takeshi Takahashi, Misako Itoh, Noriko Sakaguchi, Yuhshi Kuniyasu, Masaaki Toda, Makoto Iwata, Jun Shimizu, Shimon SakaguchiAbstract:Elimination of CD25 F T cells, which constitute 5‐10% of peripheral CD4 F T cells in normal naive mice, leads to spontaneous development of various autoimmune diseases. These immunoregulatory CD25 F CD4 F T cells are naturally unresponsive (anergic) in vitro to TCR stimulation, and, upon stimulation, suppress proliferation of CD25 ‐ CD4 F T cells and CD8 F T cells. The antigen concentration required for stimulating CD25 F CD4 F T cells to exert suppression is much lower than that required for stimulating CD25 ‐ CD4 F T cells to proliferate. The suppression, which results in reduced IL-2 production by CD25 ‐ CD4 F T cells, is dependent on cellular interactions on antigen-presenting cells (and not mediated by far-reaching or long-lasting humoral factors or apoptosis-inducing signals) and antigen non-specific in its effector phase. Addition of high doses of IL-2 or anti-CD28 antibody to the in vitro T cell stimulation culture not only breaks the anergic state of CD25 F CD4 F T cells, but also abrogates their suppressive activity simultaneously. Importantly, the anergic/suppressive state of CD25 F CD4 F T cells appeared to be their basal default condition, since removal of IL-2 or anti-CD28 antibody from the culture milieu allows them to revert to the original anergic/suppressive state. Furthermore, transfer of such anergy/suppression-broken T cells from normal mice produces various autoimmune diseases in syngeneic athymic nude mice. These results taken together indicate that one aspect of immunologic self-tolerance is maintained by this unique CD25 F CD4 F naturally anergic/
Thomas Hanke - One of the best experts on this subject based on the ideXlab platform.
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characterization of mouse cd4 t cell subsets defined by expression of klrg1
European Journal of Immunology, 2007Co-Authors: Niklas Beyersdorf, Julia K Tietze, Xin Ding, Thomas HankeAbstract:The mouse killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor known to be expressed on a subset of NK cells and antigen-experienced CD8 T cells. Here, we have characterized expression of KLRG1 on CD4+ T cells from normal mice. While a polyclonal TCR repertoire suggests thymic origin of KLRG1+ CD4+ cells, KLRG1 expression was found to be restricted to peripheral CD4+ T cells. Based on phenotypic analyses, a minority of KLRG1+ CD4+ cells are effector/memory cells with a proliferative history. The majority of KLRG1+ CD4+ cells are, however, bona fide Treg cells that depend on IL-2 and/or CD28 and express both FoxP3 and high levels of intracellular CD152. KLRG1-expressing Treg are contained within the CD38+ subset but are only partially overlapping with the CD25+ CD4+ Treg subset. In functional assays, KLRG1+ CD4+ cells were anergic to TCR stimulation with respect to proliferation, and sorted KLRG1+ CD25+ CD4+ cells were equal or superior to KLRG1+ CD25– CD4+ cells, which were more potent than KLRG1– CD25+ CD4+ cells in suppressing responder cell proliferation. Together, our results demonstrate that KLRG1 expression defines novel and distinctive subsets of senescent effector/memory and potent regulatory CD4+ T cells.
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selective targeting of regulatory t cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis
Journal of Experimental Medicine, 2005Co-Authors: Niklas Beyersdorf, Thomas Hanke, Thomas Hunig, Stefanie Gaupp, Karen Balbach, Jens Schmidt, Klaus V Toyka, Thomas Kerkau, Ralf GoldAbstract:CD4+CD25+ regulatory T cells (T reg cells) play a key role in controlling autoimmunity and inflammation. Therefore, therapeutic agents that are capable of elevating numbers or increasing effector functions of this T cell subset are highly desirable. In a previous report we showed that a superagonistic monoclonal antibody specific for rat CD28 (JJ316) expands and activates T reg cells in vivo and upon short-term in vitro culture. Here we demonstrate that application of very low dosages of the CD28 superagonist into normal Lewis rats is sufficient to induce T reg cell expansion in vivo without the generalized lymphocytosis observed with high dosages of JJ316. Single i.v. administration of a low dose of the CD28 superagonist into Dark Agouti (DA) rats or Lewis rats that suffered from experimental autoimmune encephalomyelitis (EAE) proved to be highly and equally efficacious as high-dose treatment. Finally, we show that T reg cells that were isolated from CD28-treated animals displayed enhanced suppressive activity toward myelin basic protein–specific T cells in vitro, and, upon adoptive transfer, protected recipients from EAE. Our data indicate that this class of CD28-specific monoclonal antibodies targets CD4+CD25+ T reg cells and provides a novel means for the effective treatment of multiple sclerosis and other autoimmune diseases.
Thomas Hunig - One of the best experts on this subject based on the ideXlab platform.
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selective targeting of regulatory t cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis
Journal of Experimental Medicine, 2005Co-Authors: Niklas Beyersdorf, Thomas Hanke, Thomas Hunig, Stefanie Gaupp, Karen Balbach, Jens Schmidt, Klaus V Toyka, Thomas Kerkau, Ralf GoldAbstract:CD4+CD25+ regulatory T cells (T reg cells) play a key role in controlling autoimmunity and inflammation. Therefore, therapeutic agents that are capable of elevating numbers or increasing effector functions of this T cell subset are highly desirable. In a previous report we showed that a superagonistic monoclonal antibody specific for rat CD28 (JJ316) expands and activates T reg cells in vivo and upon short-term in vitro culture. Here we demonstrate that application of very low dosages of the CD28 superagonist into normal Lewis rats is sufficient to induce T reg cell expansion in vivo without the generalized lymphocytosis observed with high dosages of JJ316. Single i.v. administration of a low dose of the CD28 superagonist into Dark Agouti (DA) rats or Lewis rats that suffered from experimental autoimmune encephalomyelitis (EAE) proved to be highly and equally efficacious as high-dose treatment. Finally, we show that T reg cells that were isolated from CD28-treated animals displayed enhanced suppressive activity toward myelin basic protein–specific T cells in vitro, and, upon adoptive transfer, protected recipients from EAE. Our data indicate that this class of CD28-specific monoclonal antibodies targets CD4+CD25+ T reg cells and provides a novel means for the effective treatment of multiple sclerosis and other autoimmune diseases.
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efficient expansion of regulatory t cells in vitro and in vivo with a CD28 superagonist
European Journal of Immunology, 2003Co-Authors: Chiahuey Lin, Thomas HunigAbstract:CD4(+)CD25(+) T cells play a central role in the suppression of autoimmunity and inflammation, making their in vivo expansion a highly attractive therapeutic target. By phenotyping with a novel rat CTL antigen-4 (CTLA-4)-specific monoclonal antibody (mAb) and functional in vitro assays, we here first establish that rat CD4(+)CD25(+) T cells correspond to the regulatory T cells (Treg cells) described in mice and humans: they constitutively express CTLA-4, produce IL-10 but not IL-2, and are able to suppress the proliferation of costimulated CD25-negative indicator cells. Furthermore, we show that rat Treg cells respond less well than CD25(-) T cells to conventional costimulation, but are readily expanded in vitro with "superagonistic" CD28-specific mAb which are potent mitogens for all T cells without the need for TCR engagement. In vivo, functional Treg cells are preferentially expanded by CD28 stimulation over other T cell subsets, leading to a 20-fold increase within 3 days in response to a single antibody dose. These data suggest that CD28-driven activation of Treg cells may be highly effective in the treatment of inflammatory and autoimmune diseases.
Takeshi Takahashi - One of the best experts on this subject based on the ideXlab platform.
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immunologic self tolerance maintained by cd25 cd4 regulatory t cells constitutively expressing cytotoxic t lymphocyte associated antigen 4
Journal of Experimental Medicine, 2000Co-Authors: Takeshi Takahashi, Noriko Sakaguchi, Jun Shimizu, Tomoyuki Tagami, Sayuri Yamazaki, Toshimitsu Uede, Tak W Mak, Shimon SakaguchiAbstract:This report shows that cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) plays a key role in T cell–mediated dominant immunologic self-tolerance. In vivo blockade of CTLA-4 for a limited period in normal mice leads to spontaneous development of chronic organ-specific autoimmune diseases, which are immunopathologically similar to human counterparts. In normal naive mice, CTLA-4 is constitutively expressed on CD25+CD4+ T cells, which constitute 5–10% of peripheral CD4+ T cells. When the CD25+CD4+ T cells are stimulated via the T cell receptor in vitro, they potently suppress antigen-specific and polyclonal activation and proliferation of other T cells, including CTLA-4–deficient T cells, and blockade of CTLA-4 abrogates the suppression. CD28-deficient CD25+CD4+ T cells can also suppress normal T cells, indicating that CD28 is dispensable for activation of the regulatory T cells. Thus, the CD25+CD4+ regulatory T cell population engaged in dominant self-tolerance may require CTLA-4 but not CD28 as a costimulatory molecule for its functional activation. Furthermore, interference with this role of CTLA-4 suffices to elicit autoimmune disease in otherwise normal animals, presumably through affecting CD25+CD4+ T cell–mediated control of self-reactive T cells. This unique function of CTLA-4 could be exploited to potentiate T cell–mediated immunoregulation, and thereby to induce immunologic tolerance or to control autoimmunity.
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immunologic self tolerance maintained by cd25 cd4 naturally anergic and suppressive t cells induction of autoimmune disease by breaking their anergic suppressive state
International Immunology, 1998Co-Authors: Takeshi Takahashi, Misako Itoh, Noriko Sakaguchi, Yuhshi Kuniyasu, Masaaki Toda, Makoto Iwata, Jun Shimizu, Shimon SakaguchiAbstract:Elimination of CD25 F T cells, which constitute 5‐10% of peripheral CD4 F T cells in normal naive mice, leads to spontaneous development of various autoimmune diseases. These immunoregulatory CD25 F CD4 F T cells are naturally unresponsive (anergic) in vitro to TCR stimulation, and, upon stimulation, suppress proliferation of CD25 ‐ CD4 F T cells and CD8 F T cells. The antigen concentration required for stimulating CD25 F CD4 F T cells to exert suppression is much lower than that required for stimulating CD25 ‐ CD4 F T cells to proliferate. The suppression, which results in reduced IL-2 production by CD25 ‐ CD4 F T cells, is dependent on cellular interactions on antigen-presenting cells (and not mediated by far-reaching or long-lasting humoral factors or apoptosis-inducing signals) and antigen non-specific in its effector phase. Addition of high doses of IL-2 or anti-CD28 antibody to the in vitro T cell stimulation culture not only breaks the anergic state of CD25 F CD4 F T cells, but also abrogates their suppressive activity simultaneously. Importantly, the anergic/suppressive state of CD25 F CD4 F T cells appeared to be their basal default condition, since removal of IL-2 or anti-CD28 antibody from the culture milieu allows them to revert to the original anergic/suppressive state. Furthermore, transfer of such anergy/suppression-broken T cells from normal mice produces various autoimmune diseases in syngeneic athymic nude mice. These results taken together indicate that one aspect of immunologic self-tolerance is maintained by this unique CD25 F CD4 F naturally anergic/
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Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state.
International Immunology, 1998Co-Authors: Takeshi Takahashi, Misako Itoh, Noriko Sakaguchi, Yuhshi Kuniyasu, Masaaki Toda, Makoto Iwata, Jun Shimizu, Shimon SakaguchiAbstract:Elimination of CD25 F T cells, which constitute 5‐10% of peripheral CD4 F T cells in normal naive mice, leads to spontaneous development of various autoimmune diseases. These immunoregulatory CD25 F CD4 F T cells are naturally unresponsive (anergic) in vitro to TCR stimulation, and, upon stimulation, suppress proliferation of CD25 ‐ CD4 F T cells and CD8 F T cells. The antigen concentration required for stimulating CD25 F CD4 F T cells to exert suppression is much lower than that required for stimulating CD25 ‐ CD4 F T cells to proliferate. The suppression, which results in reduced IL-2 production by CD25 ‐ CD4 F T cells, is dependent on cellular interactions on antigen-presenting cells (and not mediated by far-reaching or long-lasting humoral factors or apoptosis-inducing signals) and antigen non-specific in its effector phase. Addition of high doses of IL-2 or anti-CD28 antibody to the in vitro T cell stimulation culture not only breaks the anergic state of CD25 F CD4 F T cells, but also abrogates their suppressive activity simultaneously. Importantly, the anergic/suppressive state of CD25 F CD4 F T cells appeared to be their basal default condition, since removal of IL-2 or anti-CD28 antibody from the culture milieu allows them to revert to the original anergic/suppressive state. Furthermore, transfer of such anergy/suppression-broken T cells from normal mice produces various autoimmune diseases in syngeneic athymic nude mice. These results taken together indicate that one aspect of immunologic self-tolerance is maintained by this unique CD25 F CD4 F naturally anergic/
Niklas Beyersdorf - One of the best experts on this subject based on the ideXlab platform.
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characterization of mouse cd4 t cell subsets defined by expression of klrg1
European Journal of Immunology, 2007Co-Authors: Niklas Beyersdorf, Julia K Tietze, Xin Ding, Thomas HankeAbstract:The mouse killer cell lectin-like receptor G1 (KLRG1) is an inhibitory receptor known to be expressed on a subset of NK cells and antigen-experienced CD8 T cells. Here, we have characterized expression of KLRG1 on CD4+ T cells from normal mice. While a polyclonal TCR repertoire suggests thymic origin of KLRG1+ CD4+ cells, KLRG1 expression was found to be restricted to peripheral CD4+ T cells. Based on phenotypic analyses, a minority of KLRG1+ CD4+ cells are effector/memory cells with a proliferative history. The majority of KLRG1+ CD4+ cells are, however, bona fide Treg cells that depend on IL-2 and/or CD28 and express both FoxP3 and high levels of intracellular CD152. KLRG1-expressing Treg are contained within the CD38+ subset but are only partially overlapping with the CD25+ CD4+ Treg subset. In functional assays, KLRG1+ CD4+ cells were anergic to TCR stimulation with respect to proliferation, and sorted KLRG1+ CD25+ CD4+ cells were equal or superior to KLRG1+ CD25– CD4+ cells, which were more potent than KLRG1– CD25+ CD4+ cells in suppressing responder cell proliferation. Together, our results demonstrate that KLRG1 expression defines novel and distinctive subsets of senescent effector/memory and potent regulatory CD4+ T cells.
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selective targeting of regulatory t cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis
Journal of Experimental Medicine, 2005Co-Authors: Niklas Beyersdorf, Thomas Hanke, Thomas Hunig, Stefanie Gaupp, Karen Balbach, Jens Schmidt, Klaus V Toyka, Thomas Kerkau, Ralf GoldAbstract:CD4+CD25+ regulatory T cells (T reg cells) play a key role in controlling autoimmunity and inflammation. Therefore, therapeutic agents that are capable of elevating numbers or increasing effector functions of this T cell subset are highly desirable. In a previous report we showed that a superagonistic monoclonal antibody specific for rat CD28 (JJ316) expands and activates T reg cells in vivo and upon short-term in vitro culture. Here we demonstrate that application of very low dosages of the CD28 superagonist into normal Lewis rats is sufficient to induce T reg cell expansion in vivo without the generalized lymphocytosis observed with high dosages of JJ316. Single i.v. administration of a low dose of the CD28 superagonist into Dark Agouti (DA) rats or Lewis rats that suffered from experimental autoimmune encephalomyelitis (EAE) proved to be highly and equally efficacious as high-dose treatment. Finally, we show that T reg cells that were isolated from CD28-treated animals displayed enhanced suppressive activity toward myelin basic protein–specific T cells in vitro, and, upon adoptive transfer, protected recipients from EAE. Our data indicate that this class of CD28-specific monoclonal antibodies targets CD4+CD25+ T reg cells and provides a novel means for the effective treatment of multiple sclerosis and other autoimmune diseases.
