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Carl H June - One of the best experts on this subject based on the ideXlab platform.
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cord blood cd4 CD25 derived t regulatory cell lines express foxp3 protein and manifest potent suppressor function
Blood, 2004Co-Authors: Wayne R Godfrey, Bruce R. Blazar, Carl H June, Darrin J Spoden, Seth R Baker, Baoling Liu, Bruce L Levine, Stephen B PorterAbstract:CD4+CD25+ T regulatory (Treg) cells have been shown to critically regulate self and allograft tolerance in mice. Studies of human Treg cells have been hindered by low numbers present in peripheral blood and difficult purification. We found that cord blood was a superior source for Treg-cell isolation and cell line generation compared with adult blood. Cord blood CD4+CD25+ cells were readily purified and generated cell lines that consistently exhibited potent suppressor activity, with more than 95% suppression of allogeneic mixed lymphocyte reactions (MLRs) (29 of 30 donors). Cultured Treg cells blocked cytokine accumulation in MLRs, with a less robust inhibition of chemokine production. These cell lines uniformly expressed CD25, CD62L, CCR7, CD27, and intracellular cytotoxic T-lymphocyte antigen-4 (CTLA4). FoxP3 protein, but not mRNA, was specifically expressed. Upon restimulation with anti-CD3/CD28 beads, the cultured Treg cells produced minimal cytokines (interleukin-2 [IL-2], interferon-γ [IFN-γ], and IL-10) and preferentially expressed tumor growth factor-β (TGF-β) latency associated protein. Cytokine production, however, was restored to normal levels by restimulation with phorbol myristate acetate (PMA)/ionomycin. Cord blood–derived cultured suppressor cell function was predominantly independent of IL-10 and TGF-β. These results demonstrate cord blood contains a significant number of Treg precursor cells capable of potent suppressor function after culture activation. Banked cord blood specimens may serve as a readily available source of Treg cells for immunotherapy.
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regulatory cd4 CD25 t cells in tumors from patients with early stage non small cell lung cancer and late stage ovarian cancer
Cancer Research, 2001Co-Authors: Theresa J Goletz, Katia Schlienger, George Coukos, Stephen C Rubin, Larry R Kaiser, Carl H JuneAbstract:Immunosuppression may contribute to the progression of cancer. In this study we assessed the structural and functional status of T cells from tumor specimens obtained from patients with early stage non-small cell lung cancer and late-stage ovarian cancer. Although some groups have described structural alterations in the TCR in patients with other malignancies, we did not observe decreased expression of the CD3ζ subunit in the tumor-associated T cells. However, increased percentages of CD4+CD25+ T cells were observed in the non-small cell lung cancer tumor-infiltrating lymphocytes and ovarian cancer tumor-associated lymphocytes. Furthermore, these CD4+CD25+ T cells were found to secrete transforming growth factor-β, consistent with the phenotype of regulatory T cells. Despite a generalized expression of lymphocyte activation markers in the tumor-associated T-cell populations, the CD8+ T cells expressed low levels of CD25. To determine whether expression of CD25 could be restored on the CD8 cells, tumor-associated T cells were stimulated with anti-CD3 and anti-CD28 monoclonal antibodies. After stimulation, nearly all of the CD8 T cells expressed CD25. Furthermore, despite the low levels of interleukin 2, IFN-γ, and tumor necrosis factor-α secretion by the tumor-associated and peripheral blood T cells at baseline, stimulation with anti-CD3 and anti-CD28 monoclonal antibodies significantly increased the fraction of cells producing these cytokines. Thus, tumor-associated T cells from patients with early and late-stage epithelial tumors contain increased proportions of CD4+CD25+ T cells that secrete the immunosuppressive cytokine transforming growth factor-β. Furthermore, our results are consistent with previous reports showing impaired expression of CD25 on CD8+ T cells in cancer patients. Finally, increased lymphocyte costimulation provided by triggering the CD28 receptor is able to increase CD25 expression and cytokine secretion in tumor-associated T cells. These observations provide evidence for the contribution of regulatory T cells to immune dysfunction in cancer patients.
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regulatory cd4 CD25 t cells in tumors from patients with early stage non small cell lung cancer and late stage ovarian cancer
Cancer Research, 2001Co-Authors: Edward Y Woo, Theresa J Goletz, Katia Schlienger, George Coukos, Stephen C Rubin, Larry R Kaiser, Christina S Chu, Heidi Yeh, Carl H JuneAbstract:Immunosuppression may contribute to the progression of cancer. In this study we assessed the structural and functional status of T cells from tumor specimens obtained from patients with early stage non-small cell lung cancer and late-stage ovarian cancer. Although some groups have described structural alterations in the TCR in patients with other malignancies, we did not observe decreased expression of the CD3zeta subunit in the tumor-associated T cells. However, increased percentages of CD4(+)CD25(+) T cells were observed in the non-small cell lung cancer tumor-infiltrating lymphocytes and ovarian cancer tumor-associated lymphocytes. Furthermore, these CD4(+)CD25(+) T cells were found to secrete transforming growth factor-beta, consistent with the phenotype of regulatory T cells. Despite a generalized expression of lymphocyte activation markers in the tumor-associated T-cell populations, the CD8(+) T cells expressed low levels of CD25. To determine whether expression of CD25 could be restored on the CD8 cells, tumor-associated T cells were stimulated with anti-CD3 and anti-CD28 monoclonal antibodies. After stimulation, nearly all of the CD8 T cells expressed CD25. Furthermore, despite the low levels of interleukin 2, IFN-gamma, and tumor necrosis factor-alpha secretion by the tumor-associated and peripheral blood T cells at baseline, stimulation with anti-CD3 and anti-CD28 monoclonal antibodies significantly increased the fraction of cells producing these cytokines. Thus, tumor-associated T cells from patients with early and late-stage epithelial tumors contain increased proportions of CD4(+)CD25(+) T cells that secrete the immunosuppressive cytokine transforming growth factor-beta. Furthermore, our results are consistent with previous reports showing impaired expression of CD25 on CD8(+) T cells in cancer patients. Finally, increased lymphocyte costimulation provided by triggering the CD28 receptor is able to increase CD25 expression and cytokine secretion in tumor-associated T cells. These observations provide evidence for the contribution of regulatory T cells to immune dysfunction in cancer patients.
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/
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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+ T cells, which constitute 5-10% of peripheral CD4+ T cells in normal naive mice, leads to spontaneous development of various autoimmune diseases. These immunoregulatory CD25+CD4+ T cells are naturally unresponsive (anergic) in vitro to TCR stimulation, and, upon stimulation, suppress proliferation of CD25-CD4+ T cells and CD8+ T cells. The antigen concentration required for stimulating CD25+CD4+ T cells to exert suppression is much lower than that required for stimulating CD25-CD4+ T cells to proliferate. The suppression, which results in reduced IL-2 production by CD25-CD4+ 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+CD4+ T cells, but also abrogates their suppressive activity simultaneously. Importantly, the anergic/suppressive state of CD25+CD4+ 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+CD4+ naturally anergic/suppressive T cell population and its functional abnormality directly leads to the development of autoimmune disease.
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/
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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+ T cells, which constitute 5-10% of peripheral CD4+ T cells in normal naive mice, leads to spontaneous development of various autoimmune diseases. These immunoregulatory CD25+CD4+ T cells are naturally unresponsive (anergic) in vitro to TCR stimulation, and, upon stimulation, suppress proliferation of CD25-CD4+ T cells and CD8+ T cells. The antigen concentration required for stimulating CD25+CD4+ T cells to exert suppression is much lower than that required for stimulating CD25-CD4+ T cells to proliferate. The suppression, which results in reduced IL-2 production by CD25-CD4+ 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+CD4+ T cells, but also abrogates their suppressive activity simultaneously. Importantly, the anergic/suppressive state of CD25+CD4+ 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+CD4+ naturally anergic/suppressive T cell population and its functional abnormality directly leads to the development of autoimmune disease.
Theresa J Goletz - One of the best experts on this subject based on the ideXlab platform.
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regulatory cd4 CD25 t cells in tumors from patients with early stage non small cell lung cancer and late stage ovarian cancer
Cancer Research, 2001Co-Authors: Theresa J Goletz, Katia Schlienger, George Coukos, Stephen C Rubin, Larry R Kaiser, Carl H JuneAbstract:Immunosuppression may contribute to the progression of cancer. In this study we assessed the structural and functional status of T cells from tumor specimens obtained from patients with early stage non-small cell lung cancer and late-stage ovarian cancer. Although some groups have described structural alterations in the TCR in patients with other malignancies, we did not observe decreased expression of the CD3ζ subunit in the tumor-associated T cells. However, increased percentages of CD4+CD25+ T cells were observed in the non-small cell lung cancer tumor-infiltrating lymphocytes and ovarian cancer tumor-associated lymphocytes. Furthermore, these CD4+CD25+ T cells were found to secrete transforming growth factor-β, consistent with the phenotype of regulatory T cells. Despite a generalized expression of lymphocyte activation markers in the tumor-associated T-cell populations, the CD8+ T cells expressed low levels of CD25. To determine whether expression of CD25 could be restored on the CD8 cells, tumor-associated T cells were stimulated with anti-CD3 and anti-CD28 monoclonal antibodies. After stimulation, nearly all of the CD8 T cells expressed CD25. Furthermore, despite the low levels of interleukin 2, IFN-γ, and tumor necrosis factor-α secretion by the tumor-associated and peripheral blood T cells at baseline, stimulation with anti-CD3 and anti-CD28 monoclonal antibodies significantly increased the fraction of cells producing these cytokines. Thus, tumor-associated T cells from patients with early and late-stage epithelial tumors contain increased proportions of CD4+CD25+ T cells that secrete the immunosuppressive cytokine transforming growth factor-β. Furthermore, our results are consistent with previous reports showing impaired expression of CD25 on CD8+ T cells in cancer patients. Finally, increased lymphocyte costimulation provided by triggering the CD28 receptor is able to increase CD25 expression and cytokine secretion in tumor-associated T cells. These observations provide evidence for the contribution of regulatory T cells to immune dysfunction in cancer patients.
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regulatory cd4 CD25 t cells in tumors from patients with early stage non small cell lung cancer and late stage ovarian cancer
Cancer Research, 2001Co-Authors: Edward Y Woo, Theresa J Goletz, Katia Schlienger, George Coukos, Stephen C Rubin, Larry R Kaiser, Christina S Chu, Heidi Yeh, Carl H JuneAbstract:Immunosuppression may contribute to the progression of cancer. In this study we assessed the structural and functional status of T cells from tumor specimens obtained from patients with early stage non-small cell lung cancer and late-stage ovarian cancer. Although some groups have described structural alterations in the TCR in patients with other malignancies, we did not observe decreased expression of the CD3zeta subunit in the tumor-associated T cells. However, increased percentages of CD4(+)CD25(+) T cells were observed in the non-small cell lung cancer tumor-infiltrating lymphocytes and ovarian cancer tumor-associated lymphocytes. Furthermore, these CD4(+)CD25(+) T cells were found to secrete transforming growth factor-beta, consistent with the phenotype of regulatory T cells. Despite a generalized expression of lymphocyte activation markers in the tumor-associated T-cell populations, the CD8(+) T cells expressed low levels of CD25. To determine whether expression of CD25 could be restored on the CD8 cells, tumor-associated T cells were stimulated with anti-CD3 and anti-CD28 monoclonal antibodies. After stimulation, nearly all of the CD8 T cells expressed CD25. Furthermore, despite the low levels of interleukin 2, IFN-gamma, and tumor necrosis factor-alpha secretion by the tumor-associated and peripheral blood T cells at baseline, stimulation with anti-CD3 and anti-CD28 monoclonal antibodies significantly increased the fraction of cells producing these cytokines. Thus, tumor-associated T cells from patients with early and late-stage epithelial tumors contain increased proportions of CD4(+)CD25(+) T cells that secrete the immunosuppressive cytokine transforming growth factor-beta. Furthermore, our results are consistent with previous reports showing impaired expression of CD25 on CD8(+) T cells in cancer patients. Finally, increased lymphocyte costimulation provided by triggering the CD28 receptor is able to increase CD25 expression and cytokine secretion in tumor-associated T cells. These observations provide evidence for the contribution of regulatory T cells to immune dysfunction in cancer patients.
Ethan M Shevach - One of the best experts on this subject based on the ideXlab platform.
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cutting edge il 2 is critically required for the in vitro activation of cd4 CD25 t cell suppressor function
Journal of Immunology, 2004Co-Authors: Angela M Thornton, Ciriaco A Piccirillo, Erin E Donovan, Ethan M ShevachAbstract:CD4(+)CD25(+) T cells are potent immunoregulatory cells that suppress TCR-induced proliferation of CD4 and CD8 T cells in vitro by a cell contact-dependent mechanism. Addition of IL-2 or anti-CD28 abrogates CD4(+)CD25(+)-mediated suppression of proliferation and has been assumed to "break suppression." We examined IL-2 mRNA by quantitative PCR in cocultures of mouse CD4(+)CD25(+) and CD4(+)CD25(-) T cells. Although IL-2 gene transcription was inhibited in the presence or absence of exogenous IL-2, the addition of anti-CD28 stimulated endogenous IL-2 production. Surprisingly, transcription of IL-2 mRNA was also restored in the cocultures in the presence of anti-IL-2. These results are most compatible with a model in which CD4(+)CD25(+) T cells do not suppress the initial activation of CD4(+)CD25(-) T cells, but mediate their suppressive effects following production of IL-2 by the responder cells resulting in both the expansion of the CD4(+)CD25(+) T cells and the induction of their suppressor function.
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activation requirements for the induction of cd4 CD25 t cell suppressor function
European Journal of Immunology, 2004Co-Authors: Angela M Thornton, Ciriaco A Piccirillo, Ethan M ShevachAbstract:The in vivo differentiation/survival of CD4+CD25+ T suppressor cells is dependent on IL-2 and CD28-mediated costimulatory signals. To determine the cytokine and costimulatory requirements for CD25+ T cells in vitro, we established a two-stage culture system where CD25+ T cells were activated in a primary culture. In the subsequent culture, activated CD4+CD25+ cells were then mixed with responders in order to assess their suppressor function. Pre-culture of CD25+ T cells with anti-CD3 alone resulted in poor survival and minimal induction of suppressor activity. Pre-culture in the presence of anti-CD3 and IL-2 or IL-4, but not IL-6, IL-7, IL-9, IL-10 or IL-15, resulted in proliferation of the CD25+ cells and induction of potent suppressor function. Inhibition of the interaction of CD28 or cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) with CD80/CD86 in the pre-culture of CD4+CD25+ cells did not prevent the induction of suppressor function. Furthermore, the inhibition of costimulatory signals did not inhibit the ability of fresh CD25+ T cells to inhibit CD8+ responders under conditions where activation of the responders was independent of CD80/CD86. These studies support the view that activation of CD25+ T cells requires IL-2/IL-4 for their survival/differentiation into effector cells, but is independent of CD28/CTLA-4-mediated costimulation.