The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Shuji Sumitomo - One of the best experts on this subject based on the ideXlab platform.
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cd4 cd25 LAG3 t cells with a feature of th17 cells associated with systemic lupus erythematosus disease activity
Frontiers in Immunology, 2019Co-Authors: Rika Kato, Shuji Sumitomo, Shinichiro Nakachi, Yumi Tsuchida, Haruka Tsuchiya, Keiichi Sakurai, Norio Hanata, Yasuo Nagafuchi, Kanae Kubo, Shoko TateishiAbstract:Systemic lupus erythematosus (SLE) is an autoimmune disease that involves multiple immune cell subsets. We analyzed immune cell subsets in human peripheral blood mononuclear cells (PBMC) in order to identify the cells that are significantly associated with SLE disease activity and treatment. The frequencies of various subsets of CD4+ T cells, B cells, monocytes and NK cells in PBMC were assessed in 30 healthy controls (HC), 30 rheumatoid arthritis (RA) patients and 26 SLE patients using flow cytometry. The correlations between subset frequencies in SLE and clinical traits including Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) were examined. Changes in subset frequencies after the treatment in SLE patients were investigated. We focused on CD25+LAG3+ T cells and investigated their characteristics, including cytokine secretion, mRNA expression and suppression capacity. We assessed correlations between CD25+LAG3+ T cells and SLEDAI by Spearman's rank correlation coefficient. CD25+LAG3+ T cells were significantly increased in SLE whereas there were few in RA and HC groups. CD25+LAG3+ T cell frequencies were significantly correlated with SLEDAI and were increased in patients with a high SLEDAI score (> 10). CD25+LAG3+ T cells produced both IL-17 and FOXP3, expressed mRNA of both FOXP3 and RORC and lacked suppressive capacity. CD25+LAG3+ T cells were associated with disease activity of SLE. CD25+LAG3+ T cells had features of both CD25+FOXP3+ regulatory T cells (CD25+ Treg) and Th17. CD25+LAG3+ T cells could be associated with the inflammatory pathophysiology of SLE.
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interleukin 10 producing LAG3 regulatory t cells are associated with disease activity and abatacept treatment in rheumatoid arthritis
Arthritis Research & Therapy, 2017Co-Authors: Shinichiro Nakachi, Shuji Sumitomo, Yumi Tsuchida, Haruka Tsuchiya, Masanori Kono, Rika Kato, Keiichi Sakurai, Norio Hanata, Yasuo Nagafuchi, Shoko TateishiAbstract:Regulatory T cells (Tregs) play a role in the suppression of inflammation in autoimmune diseases, and lymphocyte activation gene 3 (LAG3) was reported as a marker of interleukin (IL)-10-producing Tregs. We aimed to clarify the function of human IL-10-producing CD4+CD25−LAG3+ T cells (LAG3+ Tregs) and their association with rheumatoid arthritis (RA). LAG3+ Tregs of human peripheral blood mononuclear cells (PBMCs) were cultured with B cells and follicular helper T cells to examine antibody suppression effects. The frequency of LAG3+ Tregs was evaluated in peripheral blood samples from 101 healthy donors and 85 patients with RA. In patients treated with abatacept, PBMC samples were analyzed before and after treatment. Naive CD4+ T cells were sorted and cultured in the presence of abatacept, followed by flow cytometric analysis and function assays. LAG3+ Tregs produced high amounts of IL-10 and interferon-γ, and they suppressed B-cell antibody production more strongly than CD25+ Tregs. Cell-to-cell contact was required for the suppressive function of LAG3+ Tregs. The frequency of LAG3+ Tregs was lower in patients with RA, especially those with higher Clinical Disease Activity Index scores. LAG3+ Tregs significantly increased after 6 months of abatacept treatment, whereas CD25+ Tregs generally decreased. Abatacept treatment in vitro conferred LAG3 and EGR2 expression on naive CD4+ T cells, and abatacept-treated CD4+ T cells exhibited suppressive activity. IL-10-producing LAG3+ Tregs are associated with the immunopathology and therapeutic response in RA. LAG3+ Tregs may participate in a mechanism for the anti-inflammatory and immune-modulating effects of targeted therapy for costimulation.
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identification of tonsillar cd4 cd25 LAG3 t cells as naturally occurring il 10 producing regulatory t cells in human lymphoid tissue
Journal of Autoimmunity, 2017Co-Authors: Shuji Sumitomo, Tomohisa Okamura, Hirofumi Shoda, Shinichiro Nakachi, Yumi Tsuchida, Rika Kato, Asayo Furukawa, Nobuo Kitahara, Kenji Kondo, Tatsuya YamasobaAbstract:Abstract IL-10-producing regulatory T cells (IL-10-producing Tregs) are one of the regulatory T cell subsets characterized by the production of high amounts of IL-10, the lack of FOXP3 expression and the strong immunosuppressive capabilities. IL-10-producing Tregs have been primarily reported as induced populations thus far, in part because identifying naturally occurring IL-10-producing Tregs was difficult due to the lack of definitive surface markers. Lymphocyte-activation gene 3 (LAG3) is a CD4 homologue that we have identified as being expressed on IL-10 producing Tregs. In human PBMC, LAG3 combined with CD49b efficiently identifies IL-10-producing Tregs. However, naturally occurring IL-10-producing Tregs in human secondary lymphoid tissue have not been described. In this report, we identified CD4+CD25−LAG3+ T cells in human tonsil. This T cell subset produced high amounts of IL-10 and expressed low levels of FOXP3. Surface markers and microarray analysis revealed that this is a distinct tonsillar CD4+ T cell subset. CD4+CD25−LAG3+ T cells expressed interleukin 10 (IL10), PR/SET domain 1 (PRDM1), and CD274 at high levels and chemokine receptor 5 (CXCR5) at low levels. CD4+CD25−LAG3+ T cells suppressed antibody production more efficiently than CD4+CD25+ T cells, and CD4+CD25−LAG3+ T cells induced B cell apoptosis. Moreover, analysis of humanized mice revealed that this cell subset suppressed a graft-versus-host disease (GVHD) reaction in vivo. Our study reveals the existence of naturally occurring IL-10-producing Tregs in human secondary lymphoid tissue and their function in immune regulation.
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Egr2 and Egr3 in regulatory T cells cooperatively control systemic autoimmunity through Ltbp3-mediated TGF-β3 production
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Kaoru Morita, Tomohisa Okamura, Mariko Inoue, Toshihiko Komai, Shuzo Teruya, Yukiko Iwasaki, Shuji Sumitomo, Hirofumi Shoda, Kazuhiko Yamamoto, Keishi FujioAbstract:Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by multiorgan inflammation induced by autoantibodies. Early growth response gene 2 (Egr2), a transcription factor essential for T-cell anergy induction, controls systemic autoimmunity in mice and humans. We have previously identified a subpopulation of CD4+ regulatory T cells, CD4+CD25−LAG3+ cells, that characteristically express both Egr2 and LAG3 and control mice model of lupus via TGF-β3 production. However, due to the mild phenotype of lymphocyte-specific Egr2-deficient mice, the presence of an additional regulator has been speculated. Here, we show that Egr2 and Egr3 expressed in T cells cooperatively prevent humoral immune responses by supporting TGF-β3 secretion. T cell-specific Egr2/Egr3 double-deficient (Egr2/3DKO) mice spontaneously developed an early onset lupus-like disease that was more severe than in T cell-specific Egr2-deficient mice. In accordance with the observation that CD4+CD25−LAG3+ cells from Egr2/3DKO mice completely lost the capacity to produce TGF-β3, the excessive germinal center reaction in Egr2/3DKO mice was suppressed by the adoptive transfer of WT CD4+CD25−LAG3+ cells or treatment with a TGF-β3–expressing vector. Intriguingly, latent TGF-β binding protein (Ltbp)3 expression maintained by Egr2 and Egr3 was required for TGF-β3 production from CD4+CD25−LAG3+ cells. Because Egr2 and Egr3 did not demonstrate cell intrinsic suppression of the development of follicular helper T cells, Egr2- and Egr3-dependent TGF-β3 production by CD4+CD25−LAG3+ cells is critical for controlling excessive B-cell responses. The unique attributes of Egr2/Egr3 in T cells may provide an opportunity for developing novel therapeutics for autoantibody-mediated diseases including SLE.
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the functions of cd4 cd25 LAG3 regulatory t cells and egr2 in the regulation of autoimmunity
Japanese Journal of Clinical Immunology, 2014Co-Authors: Keishi Fujio, Tomohisa Okamura, Shuji Sumitomo, Kazuhiko YamamotoAbstract:Regulatory T cells (Treg) are important mechanisms that regulate autoimmunity and CD4+CD25+Foxp3+ regulatory T cells (CD25+Treg) have been extensively investigated. Recently, we have identified CD4+CD25-LAG3+ regulatory T cells (LAG3+Treg) that express an anergy associated transcription factor Egr2. Egr2 regulates IL-10 production in response to IL-27, and Egr2-deficiency in T cells and B cells results in systemic autoimmunity with increased IL-17 production. Moreover, addition of Egr3 deficiency to Egr2-deficient mice significantly accelerates systemic autoimmunity without functional impairment of CD25+Treg, indicating cooperative autoimmune-regulation by Egr2 and Egr3. The linkage between Egr2 and systemic autoimmunity is also suggested by the fact that stimulation with Ly108, a candidate lupus susceptibility gene in lupus-prone NZM2410 mice, induces Egr2 expression in T cells. Collectively, LAG3+Treg and Egr2 are the unique regulators of autoimmunity and further examination may help to understand and control immune responses.
Seung Tae Kim - One of the best experts on this subject based on the ideXlab platform.
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abstract 1107 LAG3 in solid tumors as a potential novel immunotherapy target
Cancer Research, 2019Co-Authors: Su Jin Lee, Sunju Byeon, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Won Ki Kang, Ho Yeong Lim, Kyoungmee Kim, Seung Tae KimAbstract:We performed prospective immunohistochemical analysis of LAG3 for 430 consecutive patients with advanced gastrointestinal, genitourinary, or rare cancers between June 2012 and March 2016. Most patients (428/430, 99.5%) were evaluable for LAG3 expression by immunohistochemistry. In total, 18.5% (79/428) of the evaluated cancers expressed LAG3, including pancreatic (33.3%, 2 of 6), gastric (24.7%, 21 of 85), colorectal (23.6%, 48 of 203), melanoma (12.5%, 1 of 8), genitourinary (9.5%, 4 of 46), biliary tract (6.3%, 1 of 16), and sarcoma (5.4%, 2 of 37), but not miscellaneous (0.0%, 0 of 14) or hepatocellular (0.0%, 0 of 15) cancer. Among 149 metastatic CRC patients, there was no statistically significant difference in gender, age, primary tumor site, pathologic differentiation, KRAS and NRAS status, BRAF status, and microsatellite instability according to LAG3 status (expressed vs. non-expressed). Among 53 metastatic GC patients, LAG3 was only significantly associated with EBV status (P = .042). Our results add to the emerging literature on LAG3 expression in various cancer types and support the need for extended clinical exploration of this target for immunotherapy. Citation Format: Su Jin Lee, Sun-ju Byeon, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Won Ki Kang, Ho Yeong Lim, Kyoung-Mee Kim, Seung Tae Kim. LAG3 in Solid Tumors as a Potential Novel Immunotherapy Target [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1107.
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LAG3 in solid tumors as a potential novel immunotherapy target
Journal of Immunotherapy, 2019Co-Authors: Su Jin Lee, Sunju Byeon, Jeeyun Lee, Se Hoon Park, Joon Oh Park, Young Suk Park, Won Ki Kang, Ho Yeong Lim, Kyoungmee Kim, Seung Tae KimAbstract:We performed a prospective immunohistochemical analysis of lymphocyte activation gene 3 (LAG3) for 430 consecutive patients with advanced gastrointestinal, genitourinary, or rare cancers between June 2012 and March 2016. Most patients (428/430, 99.5%) were evaluable for LAG3 expression by immunohistochemistry. In total, 18.5% (79/428) of the evaluated cancers expressed LAG3, including pancreatic cancer (33.3%, 2/6), gastric cancer (24.7%, 21/85), colorectal cancer (23.6%, 48/203), melanoma (12.5%, 1/8), genitourinary cancer (9.5%, 4/46), biliary tract cancer (6.3%, 1/16), and sarcoma (5.4%, 2/37), but not miscellaneous (0.0%, 0/14) or hepatocellular (0.0%, 0/15) cancer. Among 149 metastatic colorectal cancer patients, there was no statistically significant difference in sex, age, primary tumor site, pathologic differentiation, KRAS and NRAS status, BRAF status, and microsatellite instability according to LAG3 status (expressed vs. nonexpressed). Among 53 metastatic gastric cancer patients, LAG3 was only significantly associated with Epstein Barr virus status (P=0.042). Our results add to the emerging literature on LAG3 expression in various cancer types and support the need for extended clinical exploration of this target for immunotherapy.
Keishi Fujio - One of the best experts on this subject based on the ideXlab platform.
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early growth response gene 2 expressing cd4 LAG3 regulatory t cells the therapeutic potential for treating autoimmune diseases
Frontiers in Immunology, 2018Co-Authors: Tomohisa Okamura, Kazuhiko Yamamoto, Keishi FujioAbstract:Regulatory T cells (Tregs) are necessary for the maintenance of immune tolerance. Tregs are divided into two major populations: one is thymus derived and the other develops in the periphery. Among these Tregs, CD4+CD25+ Tregs, which mainly originate in the thymus, have been extensively studied. Transcription factor Foxp3 is well known as a master regulatory gene for the development and function of CD4+CD25+ Tregs. On the other hand, peripheral Tregs consist of distinct cell subsets including Foxp3-dependent extrathymically developed Tregs and interleukin (IL)-10-producing type I regulatory T (Tr1) cells. Lymphocyte activation gene 3 (LAG3) and CD49b are reliable cell surface markers for Tr1 cells. CD4+CD25-LAG3+ Tregs (LAG3+ Tregs) develop in the periphery and produce a large amount of IL-10. LAG3+ Tregs characteristically express the early growth response gene 2 (Egr2), a zinc-finger transcription factor, and exhibit its suppressive activity in a Foxp3-independent manner. Although Egr2 was known to be essential for hindbrain development and myelination of the peripheral nervous system, recent studies revealed that Egr2 plays vital roles in the induction of T cell anergy and also the suppressive activities of LAG3+ Tregs. Intriguingly, forced expression of Egr2 converts naive CD4+ T cells into IL-10-producing Tregs that highly express LAG3. Among the four Egr gene family members, Egr3 is thought to compensate for the function of Egr2. Recently, we reported that LAG3+ Tregs suppress humoral immune responses via transforming growth factor β3 production in an Egr2- and Egr3-dependent manner. In this review, we focus on the role of Egr2 in Tregs and also discuss its therapeutic potential for the treatment of autoimmune diseases.
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Egr2 and Egr3 in regulatory T cells cooperatively control systemic autoimmunity through Ltbp3-mediated TGF-β3 production
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Kaoru Morita, Tomohisa Okamura, Mariko Inoue, Toshihiko Komai, Shuzo Teruya, Yukiko Iwasaki, Shuji Sumitomo, Hirofumi Shoda, Kazuhiko Yamamoto, Keishi FujioAbstract:Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by multiorgan inflammation induced by autoantibodies. Early growth response gene 2 (Egr2), a transcription factor essential for T-cell anergy induction, controls systemic autoimmunity in mice and humans. We have previously identified a subpopulation of CD4+ regulatory T cells, CD4+CD25−LAG3+ cells, that characteristically express both Egr2 and LAG3 and control mice model of lupus via TGF-β3 production. However, due to the mild phenotype of lymphocyte-specific Egr2-deficient mice, the presence of an additional regulator has been speculated. Here, we show that Egr2 and Egr3 expressed in T cells cooperatively prevent humoral immune responses by supporting TGF-β3 secretion. T cell-specific Egr2/Egr3 double-deficient (Egr2/3DKO) mice spontaneously developed an early onset lupus-like disease that was more severe than in T cell-specific Egr2-deficient mice. In accordance with the observation that CD4+CD25−LAG3+ cells from Egr2/3DKO mice completely lost the capacity to produce TGF-β3, the excessive germinal center reaction in Egr2/3DKO mice was suppressed by the adoptive transfer of WT CD4+CD25−LAG3+ cells or treatment with a TGF-β3–expressing vector. Intriguingly, latent TGF-β binding protein (Ltbp)3 expression maintained by Egr2 and Egr3 was required for TGF-β3 production from CD4+CD25−LAG3+ cells. Because Egr2 and Egr3 did not demonstrate cell intrinsic suppression of the development of follicular helper T cells, Egr2- and Egr3-dependent TGF-β3 production by CD4+CD25−LAG3+ cells is critical for controlling excessive B-cell responses. The unique attributes of Egr2/Egr3 in T cells may provide an opportunity for developing novel therapeutics for autoantibody-mediated diseases including SLE.
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the functions of cd4 cd25 LAG3 regulatory t cells and egr2 in the regulation of autoimmunity
Japanese Journal of Clinical Immunology, 2014Co-Authors: Keishi Fujio, Tomohisa Okamura, Shuji Sumitomo, Kazuhiko YamamotoAbstract:Regulatory T cells (Treg) are important mechanisms that regulate autoimmunity and CD4+CD25+Foxp3+ regulatory T cells (CD25+Treg) have been extensively investigated. Recently, we have identified CD4+CD25-LAG3+ regulatory T cells (LAG3+Treg) that express an anergy associated transcription factor Egr2. Egr2 regulates IL-10 production in response to IL-27, and Egr2-deficiency in T cells and B cells results in systemic autoimmunity with increased IL-17 production. Moreover, addition of Egr3 deficiency to Egr2-deficient mice significantly accelerates systemic autoimmunity without functional impairment of CD25+Treg, indicating cooperative autoimmune-regulation by Egr2 and Egr3. The linkage between Egr2 and systemic autoimmunity is also suggested by the fact that stimulation with Ly108, a candidate lupus susceptibility gene in lupus-prone NZM2410 mice, induces Egr2 expression in T cells. Collectively, LAG3+Treg and Egr2 are the unique regulators of autoimmunity and further examination may help to understand and control immune responses.
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cd4 cd25 LAG3 regulatory t cells controlled by the transcription factor egr 2
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Tomohisa Okamura, Shuji Sumitomo, Hirofumi Shoda, Keishi Fujio, Mihoko Shibuya, Shimon Sakaguchi, Kazuhiko YamamotoAbstract:Abstract Regulatory T cells (Tregs) are engaged in the maintenance of immunological self-tolerance and immune homeostasis. IL-10 has an important role in maintaining the normal immune state. Here, we show that IL-10-secreting Tregs can be delineated in normal mice as CD4+CD25−Foxp3− T cells that express lymphocyte activation gene 3 (LAG-3), an MHC-class-II-binding CD4 homolog. Although ≈2% of the CD4+CD25− T cell population consisted of CD4+CD25−LAG3+ T cells in the spleen, CD4+CD25−LAG3+ T cells are enriched to ≈8% in the Peyer's patch. They are hypoproliferative upon in vitro antigenic stimulation and suppress in vivo development of colitis. Gene expression analysis reveals that CD4+CD25−LAG3+ Tregs characteristically express early growth response gene 2 (Egr-2), a key molecule for anergy induction. Retroviral gene transfer of Egr-2 converts naive CD4+ T cells into the IL-10-secreting and LAG-3-expressing phenotype, and Egr-2-transduced CD4+ T cells exhibit antigen-specific immunosuppressive capacity in vivo. Unlike Foxp3+ natural Tregs, high-affinity interactions with selecting peptide/MHC ligands expressed in the thymus do not induce the development of CD4+CD25−LAG3+ Tregs. In contrast, the number of CD4+CD25−LAG3+ Tregs is influenced by the presence of environmental microbiota. Thus, IL-10-secreting Egr-2+LAG3+CD4+ Tregs can be exploited for the control of peripheral immunity.
Dario A A Vignali - One of the best experts on this subject based on the ideXlab platform.
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lymphocyte activation gene 3 LAG3 the next immune checkpoint receptor
Seminars in Immunology, 2019Co-Authors: Elisa Ruffo, Tullia C Bruno, Creg J Workman, Dario A A VignaliAbstract:Immune checkpoint therapy has revolutionized cancer treatment by blocking inhibitory pathways in T cells that limits the an effective anti-tumor immune response. Therapeutics targeting CTLA-4 and PD1/PDL1 have progressed to first line therapy in multiple tumor types with some patients exhibiting tumor regression or remission. However, the majority of patients do not benefit from checkpoint therapy emphasizing the need for alternative therapeutic options. Lymphocyte Activation Gene 3 (LAG3) or CD223 is expressed on multiple cell types including CD4+ and CD8+ T cells, and Tregs, and is required for optimal T cell regulation and homeostasis. Persistent antigen-stimulation in cancer or chronic infection leads to chronic LAG3 expression, promoting T cell exhaustion. Targeting LAG3 along with PD1 facilitates T cell reinvigoration. A substantial amount of pre-clinical data and mechanistic analysis has led to LAG3 being the third checkpoint to be targeted in the clinic with nearly a dozen therapeutics under investigation. In this review, we will discuss the structure, function and role of LAG3 in murine and human models of disease, including autoimmune and inflammatory diseases, chronic viral and parasitic infections, and cancer, emphasizing new advances in the development of LAG3-targeting immunotherapies for cancer that are currently in clinical trials.
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biology of LAG3 checkpoint blockade
Blood, 2017Co-Authors: Dario A A VignaliAbstract:Dr. Vignali will discuss the biology of the inhibitory receptor LAG3, and its contribution to T cell exhaustion and immune regulation on CD8 + and CD4 + intratumoral T cells in mouse models of cancer and autoimmunity, and in a variety of human malignancies. He will also discuss the impact of LAG3 on regulatory T cell function. Given the considerable interest in inhibitory receptors in general, and LAG3 recently, as immunotherapeutic targets, he will also discuss how differential LAG3 expression could impact responsiveness to immunotherapy. Disclosures Vignali: Potenza Therapeutics: Consultancy, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties: Licensed IP, Research Funding; Tizona Therapeutics: Consultancy, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees, Patents & Royalties, Research Funding; Oncorus: Consultancy, Equity Ownership, Membership on an entity9s Board of Directors or advisory committees; Pieris: Membership on an entity9s Board of Directors or advisory committees; FStar: Membership on an entity9s Board of Directors or advisory committees; BMS: Equity Ownership; Merck: Equity Ownership; Crescendo: Consultancy; Intellia: Consultancy; MPM: Consultancy; Onkaido/Moderna: Consultancy; Servier: Consultancy.
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LAG3 cd223 as a cancer immunotherapy target
Immunological Reviews, 2017Co-Authors: Lawrence P Andrews, Ariel E Marciscano, Charles G Drake, Dario A A VignaliAbstract:Despite the impressive impact of CTLA4 and PD1-PDL1-targeted cancer immunotherapy, a large proportion of patients with many tumor types fail to respond. Consequently, the focus has shifted to targeting alternative inhibitory receptors (IRs) and suppressive mechanisms within the tumor microenvironment. Lymphocyte activation gene-3 (LAG3) (CD223) is the third IR to be targeted in the clinic, consequently garnering considerable interest and scrutiny. LAG3 upregulation is required to control overt activation and prevent the onset of autoimmunity. However, persistent antigen exposure in the tumor microenvironment results in sustained LAG3 expression, contributing to a state of exhaustion manifest in impaired proliferation and cytokine production. The exact signaling mechanisms downstream of LAG3 and interplay with other IRs remain largely unknown. However, the striking synergy between LAG3 and PD1 observed in multiple settings, coupled with the contrasting intracellular cytoplasmic domain of LAG3 as compared with other IRs, highlights the potential uniqueness of LAG3. There are now four LAG3-targeted therapies in the clinic with many more in preclinical development, emphasizing the broad interest in this IR. Given the translational relevance of LAG3 and the heightened interest in the impact of dual LAG3/PD1 targeting in the clinic, the outcome of these trials could serve as a nexus; significantly increasing or dampening enthusiasm for subsequent targets in the cancer immunotherapeutic pipeline.
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the extent of metalloproteinase mediated LAG3 cleavage limits the efficacy of pd1 blockade
Journal for ImmunoTherapy of Cancer, 2015Co-Authors: Lawrence P Andrews, Andrea L Szymczakworkman, Creg J Workman, Dario A A VignaliAbstract:Meeting abstracts Inhibitory receptors control immune responses preventing exacerbated T cell activation and the onset of autoimmunity; however, they also limit antitumor immunity. Enhanced co-expression of PD1 and LAG3 phenotypically mark functionally exhausted tumor-specific T cells, with dual
Tomohisa Okamura - One of the best experts on this subject based on the ideXlab platform.
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early growth response gene 2 expressing cd4 LAG3 regulatory t cells the therapeutic potential for treating autoimmune diseases
Frontiers in Immunology, 2018Co-Authors: Tomohisa Okamura, Kazuhiko Yamamoto, Keishi FujioAbstract:Regulatory T cells (Tregs) are necessary for the maintenance of immune tolerance. Tregs are divided into two major populations: one is thymus derived and the other develops in the periphery. Among these Tregs, CD4+CD25+ Tregs, which mainly originate in the thymus, have been extensively studied. Transcription factor Foxp3 is well known as a master regulatory gene for the development and function of CD4+CD25+ Tregs. On the other hand, peripheral Tregs consist of distinct cell subsets including Foxp3-dependent extrathymically developed Tregs and interleukin (IL)-10-producing type I regulatory T (Tr1) cells. Lymphocyte activation gene 3 (LAG3) and CD49b are reliable cell surface markers for Tr1 cells. CD4+CD25-LAG3+ Tregs (LAG3+ Tregs) develop in the periphery and produce a large amount of IL-10. LAG3+ Tregs characteristically express the early growth response gene 2 (Egr2), a zinc-finger transcription factor, and exhibit its suppressive activity in a Foxp3-independent manner. Although Egr2 was known to be essential for hindbrain development and myelination of the peripheral nervous system, recent studies revealed that Egr2 plays vital roles in the induction of T cell anergy and also the suppressive activities of LAG3+ Tregs. Intriguingly, forced expression of Egr2 converts naive CD4+ T cells into IL-10-producing Tregs that highly express LAG3. Among the four Egr gene family members, Egr3 is thought to compensate for the function of Egr2. Recently, we reported that LAG3+ Tregs suppress humoral immune responses via transforming growth factor β3 production in an Egr2- and Egr3-dependent manner. In this review, we focus on the role of Egr2 in Tregs and also discuss its therapeutic potential for the treatment of autoimmune diseases.
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identification of tonsillar cd4 cd25 LAG3 t cells as naturally occurring il 10 producing regulatory t cells in human lymphoid tissue
Journal of Autoimmunity, 2017Co-Authors: Shuji Sumitomo, Tomohisa Okamura, Hirofumi Shoda, Shinichiro Nakachi, Yumi Tsuchida, Rika Kato, Asayo Furukawa, Nobuo Kitahara, Kenji Kondo, Tatsuya YamasobaAbstract:Abstract IL-10-producing regulatory T cells (IL-10-producing Tregs) are one of the regulatory T cell subsets characterized by the production of high amounts of IL-10, the lack of FOXP3 expression and the strong immunosuppressive capabilities. IL-10-producing Tregs have been primarily reported as induced populations thus far, in part because identifying naturally occurring IL-10-producing Tregs was difficult due to the lack of definitive surface markers. Lymphocyte-activation gene 3 (LAG3) is a CD4 homologue that we have identified as being expressed on IL-10 producing Tregs. In human PBMC, LAG3 combined with CD49b efficiently identifies IL-10-producing Tregs. However, naturally occurring IL-10-producing Tregs in human secondary lymphoid tissue have not been described. In this report, we identified CD4+CD25−LAG3+ T cells in human tonsil. This T cell subset produced high amounts of IL-10 and expressed low levels of FOXP3. Surface markers and microarray analysis revealed that this is a distinct tonsillar CD4+ T cell subset. CD4+CD25−LAG3+ T cells expressed interleukin 10 (IL10), PR/SET domain 1 (PRDM1), and CD274 at high levels and chemokine receptor 5 (CXCR5) at low levels. CD4+CD25−LAG3+ T cells suppressed antibody production more efficiently than CD4+CD25+ T cells, and CD4+CD25−LAG3+ T cells induced B cell apoptosis. Moreover, analysis of humanized mice revealed that this cell subset suppressed a graft-versus-host disease (GVHD) reaction in vivo. Our study reveals the existence of naturally occurring IL-10-producing Tregs in human secondary lymphoid tissue and their function in immune regulation.
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Egr2 and Egr3 in regulatory T cells cooperatively control systemic autoimmunity through Ltbp3-mediated TGF-β3 production
Proceedings of the National Academy of Sciences of the United States of America, 2016Co-Authors: Kaoru Morita, Tomohisa Okamura, Mariko Inoue, Toshihiko Komai, Shuzo Teruya, Yukiko Iwasaki, Shuji Sumitomo, Hirofumi Shoda, Kazuhiko Yamamoto, Keishi FujioAbstract:Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by multiorgan inflammation induced by autoantibodies. Early growth response gene 2 (Egr2), a transcription factor essential for T-cell anergy induction, controls systemic autoimmunity in mice and humans. We have previously identified a subpopulation of CD4+ regulatory T cells, CD4+CD25−LAG3+ cells, that characteristically express both Egr2 and LAG3 and control mice model of lupus via TGF-β3 production. However, due to the mild phenotype of lymphocyte-specific Egr2-deficient mice, the presence of an additional regulator has been speculated. Here, we show that Egr2 and Egr3 expressed in T cells cooperatively prevent humoral immune responses by supporting TGF-β3 secretion. T cell-specific Egr2/Egr3 double-deficient (Egr2/3DKO) mice spontaneously developed an early onset lupus-like disease that was more severe than in T cell-specific Egr2-deficient mice. In accordance with the observation that CD4+CD25−LAG3+ cells from Egr2/3DKO mice completely lost the capacity to produce TGF-β3, the excessive germinal center reaction in Egr2/3DKO mice was suppressed by the adoptive transfer of WT CD4+CD25−LAG3+ cells or treatment with a TGF-β3–expressing vector. Intriguingly, latent TGF-β binding protein (Ltbp)3 expression maintained by Egr2 and Egr3 was required for TGF-β3 production from CD4+CD25−LAG3+ cells. Because Egr2 and Egr3 did not demonstrate cell intrinsic suppression of the development of follicular helper T cells, Egr2- and Egr3-dependent TGF-β3 production by CD4+CD25−LAG3+ cells is critical for controlling excessive B-cell responses. The unique attributes of Egr2/Egr3 in T cells may provide an opportunity for developing novel therapeutics for autoantibody-mediated diseases including SLE.
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the functions of cd4 cd25 LAG3 regulatory t cells and egr2 in the regulation of autoimmunity
Japanese Journal of Clinical Immunology, 2014Co-Authors: Keishi Fujio, Tomohisa Okamura, Shuji Sumitomo, Kazuhiko YamamotoAbstract:Regulatory T cells (Treg) are important mechanisms that regulate autoimmunity and CD4+CD25+Foxp3+ regulatory T cells (CD25+Treg) have been extensively investigated. Recently, we have identified CD4+CD25-LAG3+ regulatory T cells (LAG3+Treg) that express an anergy associated transcription factor Egr2. Egr2 regulates IL-10 production in response to IL-27, and Egr2-deficiency in T cells and B cells results in systemic autoimmunity with increased IL-17 production. Moreover, addition of Egr3 deficiency to Egr2-deficient mice significantly accelerates systemic autoimmunity without functional impairment of CD25+Treg, indicating cooperative autoimmune-regulation by Egr2 and Egr3. The linkage between Egr2 and systemic autoimmunity is also suggested by the fact that stimulation with Ly108, a candidate lupus susceptibility gene in lupus-prone NZM2410 mice, induces Egr2 expression in T cells. Collectively, LAG3+Treg and Egr2 are the unique regulators of autoimmunity and further examination may help to understand and control immune responses.
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cd4 cd25 LAG3 regulatory t cells controlled by the transcription factor egr 2
Proceedings of the National Academy of Sciences of the United States of America, 2009Co-Authors: Tomohisa Okamura, Shuji Sumitomo, Hirofumi Shoda, Keishi Fujio, Mihoko Shibuya, Shimon Sakaguchi, Kazuhiko YamamotoAbstract:Abstract Regulatory T cells (Tregs) are engaged in the maintenance of immunological self-tolerance and immune homeostasis. IL-10 has an important role in maintaining the normal immune state. Here, we show that IL-10-secreting Tregs can be delineated in normal mice as CD4+CD25−Foxp3− T cells that express lymphocyte activation gene 3 (LAG-3), an MHC-class-II-binding CD4 homolog. Although ≈2% of the CD4+CD25− T cell population consisted of CD4+CD25−LAG3+ T cells in the spleen, CD4+CD25−LAG3+ T cells are enriched to ≈8% in the Peyer's patch. They are hypoproliferative upon in vitro antigenic stimulation and suppress in vivo development of colitis. Gene expression analysis reveals that CD4+CD25−LAG3+ Tregs characteristically express early growth response gene 2 (Egr-2), a key molecule for anergy induction. Retroviral gene transfer of Egr-2 converts naive CD4+ T cells into the IL-10-secreting and LAG-3-expressing phenotype, and Egr-2-transduced CD4+ T cells exhibit antigen-specific immunosuppressive capacity in vivo. Unlike Foxp3+ natural Tregs, high-affinity interactions with selecting peptide/MHC ligands expressed in the thymus do not induce the development of CD4+CD25−LAG3+ Tregs. In contrast, the number of CD4+CD25−LAG3+ Tregs is influenced by the presence of environmental microbiota. Thus, IL-10-secreting Egr-2+LAG3+CD4+ Tregs can be exploited for the control of peripheral immunity.
