糖脂質抗原α-galactosylceramideによって活性化された樹状細胞、 invariant natural killer T細胞はマウス流産を引き起こす
[目的] 近年生殖免疫において、樹状細胞(dendritic cells: DCs)やinvariant natural killer T(iNKT)細 胞など自然免疫の重要性が指摘されつつある。これまで我々は糖脂質α-galactosylceramide(α-GalCer)投与により誘導した流産マウスでは、子宮局所にDEC-205+ DCsとNK1.1+ iNKT細胞の有為な集積を報告してきたが、これら細胞の集積が流産の原因なのかそれとも結果なのかは不明であった。そこで今回我々は妊娠マウスに、予めα-GalCerを付与したDCsの養子移入を行い直接流産を誘導し得るのかを検討するとともに、原因...
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| Published in | Reproductive Immunology and Biology Vol. 34; pp. 17 - 26 |
|---|---|
| Main Authors | , , , , |
| Format | Journal Article |
| Language | Japanese |
| Published |
日本生殖免疫学会
2019
|
| Subjects | |
| Online Access | Get full text |
| ISSN | 1881-607X 1881-7211 |
| DOI | 10.3192/jsirib.34.17 |
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| Abstract | [目的] 近年生殖免疫において、樹状細胞(dendritic cells: DCs)やinvariant natural killer T(iNKT)細 胞など自然免疫の重要性が指摘されつつある。これまで我々は糖脂質α-galactosylceramide(α-GalCer)投与により誘導した流産マウスでは、子宮局所にDEC-205+ DCsとNK1.1+ iNKT細胞の有為な集積を報告してきたが、これら細胞の集積が流産の原因なのかそれとも結果なのかは不明であった。そこで今回我々は妊娠マウスに、予めα-GalCerを付与したDCsの養子移入を行い直接流産を誘導し得るのかを検討するとともに、原因不明ヒト流早産発症への考察を加えた。[方法] 非妊娠C57BL/6(B6)マウス大腿骨、頸骨より骨髄を採取、IL-4、GM-CSFの存在下およびα-GalCer有無の条件で培養し骨髄誘導樹状細胞(bone marrow-derived DCs: BMDCs)を得た。これを磁気ビーズ法によりDEC-205+(CD205+)BMDCsとdendritic cell inhibitory receptor-2(DCIR2)+ BMDCsの亜分画に分離し、それぞれ同種同系妊娠B6マウス(妊娠7.5日)に養子移入し、妊娠帰結、子宮局所の各免疫細胞をフローサイトメトリーにて解析した。また妊娠iNKT細胞欠損マウス(Jα18-/-)への、非妊娠B6マウス脾臓由来NK1.1+ iNKT細胞の養子移入により流産が誘導され得るかも検討した。[成績] DEC-205+ BMDCsはDCIR2+ BMDCsに比べα-GalCerを効率よくCD1d分子上に表出し、さらに子宮筋層、脱落膜への集積が高かった。実際α-GalCerを付与したDEC-205+ BMDCsの養子移入では高率な流産が誘導され、この際子宮局所に活性化したNK1.1+ iNKT細胞の有意な集積を認めた。さらに脾臓から採取したNK1.1+ iNKT細胞の妊娠Jα18-/-マウスへの養子移入でも、有意な流産が誘導された。[結論] α-GalCer誘導性マウス流産では、DCsやiNKT細胞が重要な働きを担う事が示唆された。自然界にはDCs-iNKT細胞系を活性化、制御しうる様々な内因性・外因性抗原が数多く存在しており、これら流早産発症に与える影響、その担い手である自然免疫の役割は今後さらに注目されると考えられる。 |
|---|---|
| AbstractList | [目的] 近年生殖免疫において、樹状細胞(dendritic cells: DCs)やinvariant natural killer T(iNKT)細 胞など自然免疫の重要性が指摘されつつある。これまで我々は糖脂質α-galactosylceramide(α-GalCer)投与により誘導した流産マウスでは、子宮局所にDEC-205+ DCsとNK1.1+ iNKT細胞の有為な集積を報告してきたが、これら細胞の集積が流産の原因なのかそれとも結果なのかは不明であった。そこで今回我々は妊娠マウスに、予めα-GalCerを付与したDCsの養子移入を行い直接流産を誘導し得るのかを検討するとともに、原因不明ヒト流早産発症への考察を加えた。[方法] 非妊娠C57BL/6(B6)マウス大腿骨、頸骨より骨髄を採取、IL-4、GM-CSFの存在下およびα-GalCer有無の条件で培養し骨髄誘導樹状細胞(bone marrow-derived DCs: BMDCs)を得た。これを磁気ビーズ法によりDEC-205+(CD205+)BMDCsとdendritic cell inhibitory receptor-2(DCIR2)+ BMDCsの亜分画に分離し、それぞれ同種同系妊娠B6マウス(妊娠7.5日)に養子移入し、妊娠帰結、子宮局所の各免疫細胞をフローサイトメトリーにて解析した。また妊娠iNKT細胞欠損マウス(Jα18-/-)への、非妊娠B6マウス脾臓由来NK1.1+ iNKT細胞の養子移入により流産が誘導され得るかも検討した。[成績] DEC-205+ BMDCsはDCIR2+ BMDCsに比べα-GalCerを効率よくCD1d分子上に表出し、さらに子宮筋層、脱落膜への集積が高かった。実際α-GalCerを付与したDEC-205+ BMDCsの養子移入では高率な流産が誘導され、この際子宮局所に活性化したNK1.1+ iNKT細胞の有意な集積を認めた。さらに脾臓から採取したNK1.1+ iNKT細胞の妊娠Jα18-/-マウスへの養子移入でも、有意な流産が誘導された。[結論] α-GalCer誘導性マウス流産では、DCsやiNKT細胞が重要な働きを担う事が示唆された。自然界にはDCs-iNKT細胞系を活性化、制御しうる様々な内因性・外因性抗原が数多く存在しており、これら流早産発症に与える影響、その担い手である自然免疫の役割は今後さらに注目されると考えられる。 |
| Author | 高橋, 秀実 根岸, 靖幸 市川, 智子 竹下, 俊行 森田, 林平 |
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| References | 7) St Louis D, Romero R, Plazyo O, Arenas-Hernandez M, Panaitescu B, Xu Y, Milovic T, Xu Z, Bhatti G, Mi QS, et al. 2016. Invariant NKT Cell Activation Induces Late Preterm Birth That Is Attenuated by Rosiglitazone. Journal of immunology. 196 (3): 1044-1059. 13) Brennan PJ, Brigl M, and Brenner MB. 2013. Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nature reviews Immunology. 13 (2): 101-117. 8) Boyson JE, Aktan I, Barkhuff DA, and Chant A. 2008. NKT cells at the maternal-fetal interface. Immunological investigations. 37 (5): 565-582. 19) Opasawatchai A, and Matangkasombut P. 2015. iNKT Cells and Their Potential Lipid Ligands during Viral Infection. Frontiers in immunology. 6: 378-386. 21) Hoya M, Nagamatsu T, Fujii T, Schust DJ, Oda H, Akiba N, Iriyama T, Kawana K, Osuga Y, and Fujii T. 2018. Impact of Th1/Th2 cytokine polarity induced by invariant NKT cells on the incidence of pregnancy loss in mice. American journal of reproductive immunology. 79 (3): e12813. 1) Plaks V, Birnberg T, Berkutzki T, Sela S, BenYashar A, Kalchenko V, Mor G, Keshet E, Dekel N, Neeman M, et al. 2008. Uterine DCs are crucial for decidua formation during embryo implantation in mice. The Journal of clinical investigation. 118 (12): 3954-3965. 10) Ichikawa T, Negishi Y, Shimizu M, Takeshita T, and Takahashi H. 2016. alpha-Galactosylceramide-activated murine NK1.1(+) invariant-NKT cells in the myometrium induce miscarriages in mice. European journal of immunology. 46 (8): 1867-1877. 15) Nadeau-Vallee M, Obari D, Palacios J, Brien ME, Duval C, Chemtob S, and Girard S. 2016. Sterile inflammation and pregnancy complications: a review. Reproduction. 152 (6): R277-R92. 14) Ito K, Karasawa M, Kawano T, Akasaka T, Koseki H, Akutsu Y, Kondo E, Sekiya S, Sekikawa K, Harada M, et al. 2000. Involvement of decidual Valpha14 NKT cells in abortion. Proceedings of the National Academy of Sciences of the United States of America. 97 (2): 740-744. 12) Arora P, Baena A, Yu KO, Saini NK, Kharkwal SS, Goldberg MF, Kunnath-Velayudhan S, Carreno LJ, Venkataswamy MM, Kim J, et al. 2014. A single subset of dendritic cells controls the cytokine bias of natural killer T cell responses to diverse glycolipid antigens. Immunity. 40 (1): 105-116. 17) Gomez-Lopez N, Romero R, Plazyo O, Panaitescu B, Furcron AE, Miller D, Roumayah T, Flom E, and Hassan SS. 2016. Intra-Amniotic Administration of HMGB1 Induces Spontaneous Preterm Labor and Birth. American journal of reproductive immunology. 75 (1): 3-7. 3) Dekel N, Gnainsky Y, Granot I, Racicot K, and Mor G. 2014. The Role of Inflammation for a Successful Implantation. American journal of reproductive immunology. 72: 141-147. 20) Brennan PJ, Tatituri RV, Brigl M, Kim EY, Tuli A, Sanderson JP, Gadola SD, Hsu FF, Besra GS, and Brenner MB. 2011. Invariant natural killer T cells recognize lipid self antigen induced by microbial danger signals. Nature immunology. 12 (12): 1202-1211. 18) Anderson BL, Teyton L, Bendelac A, and Savage PB. 2013. Stimulation of natural killer T cells by glycolipids. Molecules. 18 (12): 15662-15688. 22) Nagamatsu T, Fujii T, Schust DJ, Tsuchiya N, Tokita Y, Hoya M, Akiba N, Iriyama T, Kawana K, Osuga Y, et al. 2018. Tokishakuyakusan, a traditional Japanese medicine (Kampo) mitigates iNKT cell-mediated pregnancy loss in mice. American journal of reproductive immunology. 80 (4): e13021. 4) Shima T, Inada K, Nakashima A, Ushijima A, Ito M, Yoshino O, and Saito S. 2015. Paternal antigen-specific proliferating regulatory T cells are increased in uterine-draining lymph nodes just before implantation and in pregnant uterus just after implantation by seminal plasma-priming in allogeneic mouse pregnancy. Journal of reproductive immunology. 108: 72-82. 9) Negishi Y, Shima Y, Takeshita T, and Takahashi H. 2017. Distribution of invariant natural killer T cells and dendritic cells in late pre-term birth without acute chorioamnionitis. American journal of reproductive immunology. 77 (6): e12658. 6) Hashemi V, Dolati S, Hosseini A, Gharibi T, Danaii S, and Yousefi M. 2017. Natural killer T cells in Preeclampsia: An updated review. Biomed Pharmacother. 95: 412-8. 11) Negishi Y, Ichikawa T, Takeshita T, and Takahashi H. 2018. Miscarriage induced by adoptive transfer of dendritic cells and invariant natural killer T cells into mice. European journal of immunology. 48 (6): 937-949. 16) Zenerino C, Nuzzo AM, Giuffrida D, Biolcati M, Zicari A, Todros T, and Rolfo A. 2017. The HMGB1/RAGE Pro-Inflammatory Axis in the Human Placenta: Modulating Effect of Low Molecular Weight Heparin. Molecules. 22 (11). 5) Negishi Y, Wakabayashi A, Shimizu M, Ichikawa T, Kumagai Y, Takeshita T, and Takahashi H. 2012. Disruption of maternal immune balance maintained by innate DC subsets results in spontaneous pregnancy loss in mice. Immunobiology. 217 (10): 951-961. 2) Blois S, Alba Soto CD, Olmos S, Chuluyan E, Gentile T, Arck PC, and Margni RA. 2004. Therapy with dendritic cells influences the spontaneous resorption rate in the CBA/J x DBA/2J mouse model. American journal of reproductive immunology. 51(1): 40-48. |
| References_xml | – reference: 5) Negishi Y, Wakabayashi A, Shimizu M, Ichikawa T, Kumagai Y, Takeshita T, and Takahashi H. 2012. Disruption of maternal immune balance maintained by innate DC subsets results in spontaneous pregnancy loss in mice. Immunobiology. 217 (10): 951-961. – reference: 20) Brennan PJ, Tatituri RV, Brigl M, Kim EY, Tuli A, Sanderson JP, Gadola SD, Hsu FF, Besra GS, and Brenner MB. 2011. Invariant natural killer T cells recognize lipid self antigen induced by microbial danger signals. Nature immunology. 12 (12): 1202-1211. – reference: 2) Blois S, Alba Soto CD, Olmos S, Chuluyan E, Gentile T, Arck PC, and Margni RA. 2004. Therapy with dendritic cells influences the spontaneous resorption rate in the CBA/J x DBA/2J mouse model. American journal of reproductive immunology. 51(1): 40-48. – reference: 17) Gomez-Lopez N, Romero R, Plazyo O, Panaitescu B, Furcron AE, Miller D, Roumayah T, Flom E, and Hassan SS. 2016. Intra-Amniotic Administration of HMGB1 Induces Spontaneous Preterm Labor and Birth. American journal of reproductive immunology. 75 (1): 3-7. – reference: 19) Opasawatchai A, and Matangkasombut P. 2015. iNKT Cells and Their Potential Lipid Ligands during Viral Infection. Frontiers in immunology. 6: 378-386. – reference: 4) Shima T, Inada K, Nakashima A, Ushijima A, Ito M, Yoshino O, and Saito S. 2015. Paternal antigen-specific proliferating regulatory T cells are increased in uterine-draining lymph nodes just before implantation and in pregnant uterus just after implantation by seminal plasma-priming in allogeneic mouse pregnancy. Journal of reproductive immunology. 108: 72-82. – reference: 9) Negishi Y, Shima Y, Takeshita T, and Takahashi H. 2017. Distribution of invariant natural killer T cells and dendritic cells in late pre-term birth without acute chorioamnionitis. American journal of reproductive immunology. 77 (6): e12658. – reference: 7) St Louis D, Romero R, Plazyo O, Arenas-Hernandez M, Panaitescu B, Xu Y, Milovic T, Xu Z, Bhatti G, Mi QS, et al. 2016. Invariant NKT Cell Activation Induces Late Preterm Birth That Is Attenuated by Rosiglitazone. Journal of immunology. 196 (3): 1044-1059. – reference: 8) Boyson JE, Aktan I, Barkhuff DA, and Chant A. 2008. NKT cells at the maternal-fetal interface. Immunological investigations. 37 (5): 565-582. – reference: 13) Brennan PJ, Brigl M, and Brenner MB. 2013. Invariant natural killer T cells: an innate activation scheme linked to diverse effector functions. Nature reviews Immunology. 13 (2): 101-117. – reference: 16) Zenerino C, Nuzzo AM, Giuffrida D, Biolcati M, Zicari A, Todros T, and Rolfo A. 2017. The HMGB1/RAGE Pro-Inflammatory Axis in the Human Placenta: Modulating Effect of Low Molecular Weight Heparin. Molecules. 22 (11). – reference: 15) Nadeau-Vallee M, Obari D, Palacios J, Brien ME, Duval C, Chemtob S, and Girard S. 2016. Sterile inflammation and pregnancy complications: a review. Reproduction. 152 (6): R277-R92. – reference: 12) Arora P, Baena A, Yu KO, Saini NK, Kharkwal SS, Goldberg MF, Kunnath-Velayudhan S, Carreno LJ, Venkataswamy MM, Kim J, et al. 2014. A single subset of dendritic cells controls the cytokine bias of natural killer T cell responses to diverse glycolipid antigens. Immunity. 40 (1): 105-116. – reference: 18) Anderson BL, Teyton L, Bendelac A, and Savage PB. 2013. Stimulation of natural killer T cells by glycolipids. Molecules. 18 (12): 15662-15688. – reference: 10) Ichikawa T, Negishi Y, Shimizu M, Takeshita T, and Takahashi H. 2016. alpha-Galactosylceramide-activated murine NK1.1(+) invariant-NKT cells in the myometrium induce miscarriages in mice. European journal of immunology. 46 (8): 1867-1877. – reference: 1) Plaks V, Birnberg T, Berkutzki T, Sela S, BenYashar A, Kalchenko V, Mor G, Keshet E, Dekel N, Neeman M, et al. 2008. Uterine DCs are crucial for decidua formation during embryo implantation in mice. The Journal of clinical investigation. 118 (12): 3954-3965. – reference: 21) Hoya M, Nagamatsu T, Fujii T, Schust DJ, Oda H, Akiba N, Iriyama T, Kawana K, Osuga Y, and Fujii T. 2018. Impact of Th1/Th2 cytokine polarity induced by invariant NKT cells on the incidence of pregnancy loss in mice. American journal of reproductive immunology. 79 (3): e12813. – reference: 11) Negishi Y, Ichikawa T, Takeshita T, and Takahashi H. 2018. Miscarriage induced by adoptive transfer of dendritic cells and invariant natural killer T cells into mice. European journal of immunology. 48 (6): 937-949. – reference: 22) Nagamatsu T, Fujii T, Schust DJ, Tsuchiya N, Tokita Y, Hoya M, Akiba N, Iriyama T, Kawana K, Osuga Y, et al. 2018. Tokishakuyakusan, a traditional Japanese medicine (Kampo) mitigates iNKT cell-mediated pregnancy loss in mice. American journal of reproductive immunology. 80 (4): e13021. – reference: 14) Ito K, Karasawa M, Kawano T, Akasaka T, Koseki H, Akutsu Y, Kondo E, Sekiya S, Sekikawa K, Harada M, et al. 2000. Involvement of decidual Valpha14 NKT cells in abortion. Proceedings of the National Academy of Sciences of the United States of America. 97 (2): 740-744. – reference: 3) Dekel N, Gnainsky Y, Granot I, Racicot K, and Mor G. 2014. The Role of Inflammation for a Successful Implantation. American journal of reproductive immunology. 72: 141-147. – reference: 6) Hashemi V, Dolati S, Hosseini A, Gharibi T, Danaii S, and Yousefi M. 2017. Natural killer T cells in Preeclampsia: An updated review. Biomed Pharmacother. 95: 412-8. |
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| SubjectTerms | 自然免疫、樹状細胞、invariant natural killer(iNKT)細胞、流早産 |
| Title | 糖脂質抗原α-galactosylceramideによって活性化された樹状細胞、 invariant natural killer T細胞はマウス流産を引き起こす |
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| ispartofPNX | Reproductive Immunology and Biology, 2019, Vol.34, pp.17-26 |
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