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Article ; Online: Editorial: Oral mucosal immunity: homeostasis and inflammation.

Zhang, Dunfang / Xu, Junji / Wang, Zhi / Nakatsukasa, Hiroko

2023 Volume 14, Page(s) 1214926

MeSH term(s)	Humans ; Immunity, Mucosal ; Inflammation ; Mouth Mucosa ; Homeostasis
Language	English
Publishing date	2023-06-06
Publishing country	Switzerland
Document type	Editorial ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1214926
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Article ; Online: Sialyl Lewis X Defines an Activated and Functional Regulatory T Cell Subpopulation in Mice.

Ohishi, Kanae / Ishikura, Asaki / Nishida, Shogo / Abo, Hirohito / Nakatsukasa, Hiroko / Kawashima, Hiroto

Journal of immunology (Baltimore, Md. : 1950)

2024

Abstract: Attempts have been made to elucidate the functional markers of regulatory T cells (Tregs), CD4+Foxp3+ T cells with an immunosuppressive function. Sialyl Lewis X (sLex), a tetrasaccharide Ag, is involved in leukocyte trafficking as selectin ligands and is ...

Abstract	Attempts have been made to elucidate the functional markers of regulatory T cells (Tregs), CD4+Foxp3+ T cells with an immunosuppressive function. Sialyl Lewis X (sLex), a tetrasaccharide Ag, is involved in leukocyte trafficking as selectin ligands and is a marker of highly differentiated Tregs in humans. However, the importance of sLex in murine Tregs remains unknown. In this study, we report that sLex defines the activated and functional subset of murine Tregs. The contact hypersensitivity model showed that murine Tregs strongly express sLex upon activation, accompanied by functional Treg marker elevation, such as Foxp3, CD25, CD103, CD39, and granzyme B. RNA sequencing analysis revealed sLex-positive (sLex+) Tregs expressed genes involved in Treg function at a higher level than sLex-negative (sLex-) Tregs. Using an in vitro suppression assay, we found that sLex+ Tregs could more efficiently suppress naive CD4+ T cell proliferation than sLex- Tregs. In the murine contact hypersensitivity elicitation model, the topical sLex+ Treg injection into the ears suppressed ear inflammation more efficiently than that of sLex- Tregs. Our results indicate that sLex could serve as a unique surface marker of activated and functional Tregs with immunosuppressive functions in mice.
Language	English
Publishing date	2024-04-19
Publishing country	United States
Document type	Journal Article
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2300349
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Article ; Online: Prevention of experimental autoimmune encephalomyelitis by targeting 6-sulfo sialyl Lewis X glycans involved in lymphocyte homing.

Liu, Qianqian / Xiong, Wei / Obara, Sachiyo / Abo, Hirohito / Nakatsukasa, Hiroko / Kawashima, Hiroto

International immunology

2024 Volume 36, Issue 6, Page(s) 303–316

Abstract: Lymphocyte homing to peripheral lymph nodes (PLN) is critical for immune surveillance. However, autoimmune diseases such as multiple sclerosis (MS) can occur due to excessive immune responses in the PLN. Here we show that 6-sulfo sialyl Lewis X (6-sulfo ... ...

Abstract	Lymphocyte homing to peripheral lymph nodes (PLN) is critical for immune surveillance. However, autoimmune diseases such as multiple sclerosis (MS) can occur due to excessive immune responses in the PLN. Here we show that 6-sulfo sialyl Lewis X (6-sulfo sLex) glycans on high endothelial venules that function as ligands for l-selectin on lymphocytes play a critical role in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In N-acetylglucosamine-6-O-sulfotransferase (GlcNAc6ST)-1 and GlcNAc6ST-2 double-knockout mice lacking the expression of 6-sulfo sLeX glycans, the EAE symptoms and the numbers of effector Th1 and Th17 cells in the draining lymph nodes (dLN) and spinal cords (SC) were significantly reduced. To determine whether 6-sulfo sLeX could serve as a target for MS, we also examined the effects of anti-glycan monoclonal antibody (mAb) SF1 against 6-sulfo sLeX in EAE. Administration of mAb SF1 significantly reduced EAE symptoms and the numbers of antigen-specific effector T cells in the dLN and SC in association with suppression of critical genes including Il17a and Il17f that are involved in the pathogenesis of EAE. Taken together, these results suggest that 6-sulfo sLeX glycan would serve as a novel target for MS.
MeSH term(s)	Animals ; Encephalomyelitis, Autoimmune, Experimental/immunology ; Mice ; Mice, Knockout ; Th17 Cells/immunology ; Sialyl Lewis X Antigen/analogs & derivatives ; Sialyl Lewis X Antigen/metabolism ; Mice, Inbred C57BL ; Polysaccharides/metabolism ; Interleukin-17/metabolism ; Interleukin-17/immunology ; Oligosaccharides ; Carbohydrate Sulfotransferases ; Th1 Cells/immunology ; Sulfotransferases/metabolism ; Sulfotransferases/genetics ; Sulfotransferases/immunology ; Lymph Nodes/immunology ; Lymph Nodes/metabolism ; Female ; Multiple Sclerosis/immunology ; Multiple Sclerosis/metabolism ; Spinal Cord/immunology ; Spinal Cord/metabolism ; Cell Movement/immunology
Chemical Substances	Sialyl Lewis X Antigen ; Polysaccharides ; Interleukin-17 ; Oligosaccharides ; Carbohydrate Sulfotransferases (EC 2.8.2.-) ; Sulfotransferases (EC 2.8.2.-) ; 6'-sulfated sialyl Lewis x
Language	English
Publishing date	2024-02-22
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1013745-2
ISSN	1460-2377 ; 0953-8178
ISSN (online)	1460-2377
ISSN	0953-8178
DOI	10.1093/intimm/dxae009
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Zs.A 2619: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Editorial: Hexose Uptake and Metabolism in Immune Homeostasis and Inflammation.

Zhang, Dunfang / Liu, Chaohong / Nakatsukasa, Hiroko / Chen, WanJun

Frontiers in immunology

2022 Volume 12, Page(s) 832293

MeSH term(s)	Animals ; Biomarkers ; Carbohydrate Metabolism ; Disease Susceptibility ; Hexoses/metabolism ; Homeostasis/immunology ; Humans ; Immune System ; Inflammation/etiology ; Inflammation/metabolism
Chemical Substances	Biomarkers ; Hexoses
Language	English
Publishing date	2022-01-10
Publishing country	Switzerland
Document type	Editorial ; Introductory Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.832293
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Article ; Online: SOCS1 Is a Key Molecule That Prevents Regulatory T Cell Plasticity under Inflammatory Conditions.

Takahashi, Reiko / Nakatsukasa, Hiroko / Shiozawa, Shunichi / Yoshimura, Akihiko

Journal of immunology (Baltimore, Md. : 1950)

2017 Volume 199, Issue 1, Page(s) 149–158

Abstract: We previously showed that regulatory T cells (Tregs) from T cell- ... ...

Abstract	We previously showed that regulatory T cells (Tregs) from T cell-specific
MeSH term(s)	Animals ; Cell Plasticity ; Cytokines/immunology ; Forkhead Transcription Factors/deficiency ; Forkhead Transcription Factors/genetics ; Forkhead Transcription Factors/metabolism ; Inflammation/immunology ; Interferon-gamma/biosynthesis ; Interferon-gamma/immunology ; Mice ; Mice, Knockout ; Splenomegaly/immunology ; Suppressor of Cytokine Signaling 1 Protein/deficiency ; Suppressor of Cytokine Signaling 1 Protein/metabolism ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/physiology
Chemical Substances	Cytokines ; Forkhead Transcription Factors ; Foxp3 protein, mouse ; Socs1 protein, mouse ; Suppressor of Cytokine Signaling 1 Protein ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2017-07-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.1600441
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Article: Role of ATP as a Key Signaling Molecule Mediating Radiation-Induced Biological Effects.

Kojima, Shuji / Ohshima, Yasuhiro / Nakatsukasa, Hiroko / Tsukimoto, Mitsutoshi

Dose-response : a publication of International Hormesis Society

2017 Volume 15, Issue 1, Page(s) 1559325817690638

Abstract: Adenosine triphosphate (ATP) serves as a signaling molecule for adaptive responses to a variety of cytotoxic agents and plays an important role in mediating the radiation stress-induced responses that serve to mitigate or repair the injurious effects of ... ...

Abstract	Adenosine triphosphate (ATP) serves as a signaling molecule for adaptive responses to a variety of cytotoxic agents and plays an important role in mediating the radiation stress-induced responses that serve to mitigate or repair the injurious effects of γ radiation on the body. Indeed, low doses of radiation may have a net beneficial effect by activating a variety of protective mechanisms, including antitumor immune responses. On the other hand, ATP signaling may be involved in the radiation resistance of cancer cells. Here, focusing on our previous work, we review the evidence that low-dose γ irradiation (0.25-0.5 Gy) induces release of extracellular ATP, and that the released ATP mediates multiple radiation-induced responses, including increased intracellular antioxidant synthesis, cell-mediated immune responses, induction of DNA damage repair systems, and differentiation of regulatory T cells.
Language	English
Publishing date	2017-02-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2440820-7
ISSN	1559-3258 ; 1559-3258
ISSN (online)	1559-3258
ISSN	1559-3258
DOI	10.1177/1559325817690638
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Article ; Online: Reprogramming of Th1 cells into regulatory T cells through rewiring of the metabolic status.

Kanamori, Mitsuhiro / Nakatsukasa, Hiroko / Ito, Minako / Chikuma, Shunsuke / Yoshimura, Akihiko

International immunology

2018 Volume 30, Issue 8, Page(s) 357–373

Abstract: T helper type 1 (Th1) cells form one of the most stable CD4 T-cell subsets, and direct conversion of fully differentiated Th1 to regulatory T (Treg) cells has been poorly investigated. Here, we established a culture method for inducing Foxp3 from Th1 ... ...

Abstract	T helper type 1 (Th1) cells form one of the most stable CD4 T-cell subsets, and direct conversion of fully differentiated Th1 to regulatory T (Treg) cells has been poorly investigated. Here, we established a culture method for inducing Foxp3 from Th1 cells of mice and humans. This is achieved simply by resting Th1 cells without T-cell receptor ligation before stimulation in the presence of transforming growth factor-beta (TGF-β). We named the resulting Th1-derived Foxp3+ cells Th1reg cells. Mouse Th1reg cells showed an inducible Treg-like phenotype and suppressive ability both in vitro and in vivo. Th1reg cells could also be induced from in vivo-developed mouse Th1 cells. Unexpectedly, the resting process enabled Foxp3 expression not through epigenetic changes at the locus, but through metabolic change resulting from reduced mammalian target of rapamycin complex 1 (mTORC1) activity. mTORC1 suppressed TGF-β-induced phosphorylation of Smad2/3 in Th1 cells, which was restored in rested cells. Our study warrants future research aiming at development of immunotherapy with Th1reg cells.
MeSH term(s)	Adult ; Animals ; Cellular Reprogramming ; Humans ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; T-Lymphocytes, Regulatory/cytology ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism ; Th1 Cells/cytology ; Th1 Cells/immunology ; Th1 Cells/metabolism
Language	English
Publishing date	2018-06-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1013745-2
ISSN	1460-2377 ; 0953-8178
ISSN (online)	1460-2377
ISSN	0953-8178
DOI	10.1093/intimm/dxy043
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Article ; Online: Negative Regulation of Cytokine Signaling in Immunity.

Yoshimura, Akihiko / Ito, Minako / Chikuma, Shunsuke / Akanuma, Takashi / Nakatsukasa, Hiroko

Cold Spring Harbor perspectives in biology

2018 Volume 10, Issue 7

Abstract: Cytokines are key modulators of immunity. Most cytokines use the Janus kinase and signal transducers and activators of transcription (JAK-STAT) pathway to promote gene transcriptional regulation, but their signals must be attenuated by multiple ... ...

Abstract	Cytokines are key modulators of immunity. Most cytokines use the Janus kinase and signal transducers and activators of transcription (JAK-STAT) pathway to promote gene transcriptional regulation, but their signals must be attenuated by multiple mechanisms. These include the suppressors of cytokine signaling (SOCS) family of proteins, which represent a main negative regulation mechanism for the JAK-STAT pathway. Cytokine-inducible Src homology 2 (SH2)-containing protein (CIS), SOCS1, and SOCS3 proteins regulate cytokine signals that control the polarization of CD4
MeSH term(s)	Animals ; Cytokines/genetics ; Cytokines/metabolism ; Gene Expression Regulation/immunology ; Humans ; Signal Transduction/immunology
Chemical Substances	Cytokines
Language	English
Publishing date	2018-07-02
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ISSN	1943-0264
ISSN (online)	1943-0264
DOI	10.1101/cshperspect.a028571
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Article ; Online: Roles of transcription factors and epigenetic modifications in differentiation and maintenance of regulatory T cells.

Sekiya, Takashi / Nakatsukasa, Hiroko / Lu, Qianjin / Yoshimura, Akihiko

Microbes and infection

2016 Volume 18, Issue 6, Page(s) 378–386

Abstract: Regulatory T (Treg) cells are an essential cell subset for the maintenance of immune homeostasis. Treg cells are characterized by a distinct pattern of gene expression, including the upregulation of immune-suppressive genes and the silencing of ... ...

Abstract	Regulatory T (Treg) cells are an essential cell subset for the maintenance of immune homeostasis. Treg cells are characterized by a distinct pattern of gene expression, including the upregulation of immune-suppressive genes and the silencing of inflammatory genes. The molecular mechanisms involved in the development and maintenance of Tregs have been extensively investigated. We have identified essential transcription factors NR4a and Smad2/3 in the development of thymic Tregs and induced Tregs, respectively. This article reviews the roles of transcription factors in the differentiation, maintenance, and function of Treg cells.
MeSH term(s)	Animals ; Cell Differentiation ; Epigenesis, Genetic ; Gene Expression Regulation ; Homeostasis ; Humans ; Nuclear Receptor Subfamily 4, Group A, Member 1/metabolism ; Smad2 Protein/metabolism ; Smad3 Protein/metabolism ; T-Lymphocytes, Regulatory/physiology ; Transcription, Genetic
Chemical Substances	Nuclear Receptor Subfamily 4, Group A, Member 1 ; Smad2 Protein ; Smad3 Protein
Language	English
Publishing date	2016-06
Publishing country	France
Document type	Journal Article ; Review
ZDB-ID	1465093-9
ISSN	1769-714X ; 1286-4579
ISSN (online)	1769-714X
ISSN	1286-4579
DOI	10.1016/j.micinf.2016.02.004
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Article ; Online: Stabilization of Foxp3 expression by CRISPR-dCas9-based epigenome editing in mouse primary T cells.

Okada, Masahiro / Kanamori, Mitsuhiro / Someya, Kazue / Nakatsukasa, Hiroko / Yoshimura, Akihiko

Epigenetics & chromatin

2017 Volume 10, Page(s) 24

Abstract: Background: Epigenome editing is expected to manipulate transcription and cell fates and to elucidate the gene expression mechanisms in various cell types. For functional epigenome editing, assessing the chromatin context-dependent activity of ... ...

Abstract	Background: Epigenome editing is expected to manipulate transcription and cell fates and to elucidate the gene expression mechanisms in various cell types. For functional epigenome editing, assessing the chromatin context-dependent activity of artificial epigenetic modifier is required. Results: In this study, we applied clustered regularly interspaced short palindromic repeats (CRISPR)-dCas9-based epigenome editing to mouse primary T cells, focusing on the Conclusions: Our results showed that artificial epigenome editing modified the epigenetic status and gene expression of the targeted loci, and engineered cellular functions in conjunction with endogenous epigenetic modification, suggesting effective usage of these technologies, which help elucidate the relationship between chromatin states and gene expression.
MeSH term(s)	Animals ; CRISPR-Cas Systems/genetics ; DNA Methylation/genetics ; DNA-Binding Proteins/genetics ; E1A-Associated p300 Protein/genetics ; Epigenomics ; Forkhead Transcription Factors/biosynthesis ; Forkhead Transcription Factors/genetics ; Gene Editing ; Gene Expression Regulation/genetics ; Mice ; Promoter Regions, Genetic ; Proto-Oncogene Proteins/genetics ; T-Lymphocytes, Regulatory/metabolism ; Transforming Growth Factor beta/genetics
Chemical Substances	DNA-Binding Proteins ; Forkhead Transcription Factors ; Foxp3 protein, mouse ; Proto-Oncogene Proteins ; TET1 protein, mouse ; Transforming Growth Factor beta ; E1A-Associated p300 Protein (EC 2.3.1.48) ; EP300 protein, human (EC 2.3.1.48)
Language	English
Publishing date	2017
Publishing country	England
Document type	Journal Article
ZDB-ID	2462129-8
ISSN	1756-8935 ; 1756-8935
ISSN (online)	1756-8935
ISSN	1756-8935
DOI	10.1186/s13072-017-0129-1
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