The Tokushima journal of experimental medicine最新文献_第4页

Correction: Suppressive effects of the obese tumor microenvironment on CD8 T cell infiltration and effector function 更正:肥胖肿瘤微环境对CD8 T细胞浸润及效应物功能的抑制作用

The Tokushima journal of experimental medicine Pub Date : 2022-02-28 DOI: 10.1084/jem.2021004202072022c

L. Dyck, Hannah Prendeville, Mathilde Raverdeau, Mieszko M. Wilk, Roisín M Loftus, A. Douglas, J. McCormack, Bruce Moran, M. Wilkinson, E. Mills, Michael Doughty, A. Fabre, Helen Heneghan, C. LeRoux, A. Hogan, Edward T. Chouchani, Donal O'Shea, Donal J Brennan, L. Lynch

引用次数: 4

Disruption of thymic central tolerance by infection with murine roseolovirus induces autoimmune gastritis 小鼠玫瑰病毒感染破坏胸腺中枢耐受诱导自身免疫性胃炎

The Tokushima journal of experimental medicine Pub Date : 2022-02-26 DOI: 10.1084/jem.20211403

T. Bigley, Liping Yang, L. Kang, J. Saenz, F. Victorino, W. Yokoyama

引用次数: 12

P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and virus infection 核糖毒性应激反应和病毒感染后，P38激酶介导NLRP1炎性体活化

The Tokushima journal of experimental medicine Pub Date : 2022-01-25 DOI: 10.1101/2022.01.24.477423

Lea-Marie Jenster, Karl-Elmar Lange, S. Normann, Anja vom Hemdt, J. D. Wuerth, L. Schiffelers, Y. Tesfamariam, F. N. Gohr, Laura B. C. Klein, I. H. Kaltheuner, Dorothee Johanna Lapp, Jacob Mayer, Jonas Moecking, H. Ploegh, E. Latz, M. Geyer, B. Kümmerer, F. Schmidt

{"title":"P38 kinases mediate NLRP1 inflammasome activation after ribotoxic stress response and virus infection","authors":"Lea-Marie Jenster, Karl-Elmar Lange, S. Normann, Anja vom Hemdt, J. D. Wuerth, L. Schiffelers, Y. Tesfamariam, F. N. Gohr, Laura B. C. Klein, I. H. Kaltheuner, Dorothee Johanna Lapp, Jacob Mayer, Jonas Moecking, H. Ploegh, E. Latz, M. Geyer, B. Kümmerer, F. Schmidt","doi":"10.1101/2022.01.24.477423","DOIUrl":"https://doi.org/10.1101/2022.01.24.477423","url":null,"abstract":"Inflammasomes integrate cytosolic evidence of infection or damage to mount inflammatory responses. The inflammasome sensor NLRP1 is expressed in human keratinocytes and coordinates inflammation in the skin. We found that diverse stress signals converge on the activation of p38 kinases to initiate human NLRP1 inflammasome assembly: UV irradiation and microbial molecules that initiate the ribotoxic stress response critically relied on the MAP3 kinase ZAKα to activate p38 and ultimately human NLRP1. Infection with insect-transmitted alphaviruses, including Semliki Forest, Ross River, and Chikungunya virus, also activated NLRP1 in a p38-dependent manner. In the absence on ZAKα, inflammasome assembly was maintained, although at reduced levels, indicating contribution of other upstream kinases. NLRP1 activation by direct nanobody-mediated ubiquitination was independent of p38 activity. Stimulation of p38 by overexpression of MAP2 kinases MKK3 or MKK6 is sufficient for NLRP1 activation, and NLRP1 is directly phosphorylated by p38. Taken together, we define p38 activation as a unifying signaling hub that controls NLRP1 inflammasome activation by integrating a variety of cellular stress signals relevant to the skin.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2022-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80098460","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 27

Phostensin enables lymphocyte integrin activation and population of peripheral lymphoid organs Phostensin促进淋巴细胞整合素的激活和外周血淋巴器官的聚集

The Tokushima journal of experimental medicine Pub Date : 2021-09-24 DOI: 10.1101/2021.09.24.461584

Ho-Sup Lee, Hao Sun, F. Lagarrigue, J. Fox, N. Sherman, A. Gingras, M. Ginsberg

{"title":"Phostensin enables lymphocyte integrin activation and population of peripheral lymphoid organs","authors":"Ho-Sup Lee, Hao Sun, F. Lagarrigue, J. Fox, N. Sherman, A. Gingras, M. Ginsberg","doi":"10.1101/2021.09.24.461584","DOIUrl":"https://doi.org/10.1101/2021.09.24.461584","url":null,"abstract":"Rap1 GTPase drives assembly of the Mig-10/RIAM/lamellipodin–Integrin–Talin (MIT) complex that enables integrin-dependent lymphocyte functions. Here we used tandem affinity tag-based proteomics to isolate and analyze the MIT complex and reveal that Phostensin (PTSN), a regulatory subunit of protein phosphatase 1, is a component of the complex. PTSN mediates de-phosphorylation of Rap1 thereby preserving the activity and membrane localization of Rap1 to stabilize the MIT complex. CRISPR/Cas9-induced deletion of PPP1R18, which encodes PTSN, markedly suppresses integrin activation in Jurkat human T cells. We generated apparently healthy Ppp1r18-/- mice that manifest lymphocytosis and reduced population of peripheral lymphoid tissues ascribable to defective activation of integrins αLβ2 and α4β7. Ppp1r18-/- T cells exhibit reduced capacity to induce colitis in a murine adoptive transfer model. Thus, PTSN enables lymphocyte integrin-mediated functions by dephosphorylating Rap1 to stabilize the MIT complex. As a consequence, loss of PTSN ameliorates T cell-mediated colitis. SUMMARY Phostensin, a protein phosphatase 1 regulatory subunit, supports lymphocyte integrin-dependent functions by mediating dephosphorylation of Rap1 to stabilize the MIT complex thereby enabling the population of peripheral lymphoid organs and T cell-mediated colitis.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"72 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73599655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 1

WDR82-binding long noncoding RNA lncEry controls mouse erythroid differentiation and maturation 结合wdr82的长链非编码RNA lncEry控制小鼠红细胞的分化和成熟

The Tokushima journal of experimental medicine Pub Date : 2021-07-13 DOI: 10.1101/2021.07.13.452142

Shangda Yang, Guohuan Sun, Peng Wu, Cong Chen, Yijin Kuang, Ling Liu, Zhaofeng Zheng, Yi-Di He, Quan Gu, Ting Lu, Caiying Zhu, Fengjiao Wang, Fanglin Gou, Zining Yang, Xiangnan Zhao, Shiru Yuan, Liu Yang, Shihong Lu, Yapu Li, Xue Lv, F. Dong, Yanni Ma, Jia Yu, L. Ng, Lihong Shi, Jing Liu, Lei Shi, T. Cheng, Hui Cheng

{"title":"WDR82-binding long noncoding RNA lncEry controls mouse erythroid differentiation and maturation","authors":"Shangda Yang, Guohuan Sun, Peng Wu, Cong Chen, Yijin Kuang, Ling Liu, Zhaofeng Zheng, Yi-Di He, Quan Gu, Ting Lu, Caiying Zhu, Fengjiao Wang, Fanglin Gou, Zining Yang, Xiangnan Zhao, Shiru Yuan, Liu Yang, Shihong Lu, Yapu Li, Xue Lv, F. Dong, Yanni Ma, Jia Yu, L. Ng, Lihong Shi, Jing Liu, Lei Shi, T. Cheng, Hui Cheng","doi":"10.1101/2021.07.13.452142","DOIUrl":"https://doi.org/10.1101/2021.07.13.452142","url":null,"abstract":"Hematopoietic differentiation is controlled by both genetic and epigenetic regulators. Long non-coding RNAs (lncRNAs) have been demonstrated to be important for normal hematopoiesis, but their function in erythropoiesis needs to be further explored. We profiled the transcriptomes of 16 murine hematopoietic cell populations by deep RNA-sequencing and identified a novel lncRNA, Gm15915, that was highly expressed in erythroid-related progenitors and erythrocytes. For this reason, we named it lncEry. We also identified a novel lncEry isoform, which was also the principal transcript that has not been reported before. LncEry depletion impaired erythropoiesis, indicating the important role of the lncRNA in regulating erythroid differentiation and maturation. Mechanistically, we found that lncEry interacted with WD repeat-containing protein 82 (WDR82) to promote the transcription of Klf1 and globin genes and thus control the early and late stages of erythropoiesis, respectively. These findings identified lncEry as an important player in the transcriptional regulation of erythropoiesis.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76378910","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 3

Molecular architecture determines brain delivery of a transferrin receptor–targeted lysosomal enzyme 分子结构决定脑传递转铁蛋白受体靶向溶酶体酶

The Tokushima journal of experimental medicine Pub Date : 2021-05-22 DOI: 10.1084/jem.20211057

A. Arguello, Cathal S. Mahon, M. E. Calvert, D. Chan, J. Dugas, Michelle E Pizzo, Elliot R. Thomsen, Roni Chau, Lorna A Damo, Joseph Duque, Meng Fang, T. Giese, Do Jin Kim, Nicholas Liang, Hoang N. Nguyen, Hilda Solanoy, Buyankhishig Tsogtbaatar, J. Ullman, Junhua Wang, M. Dennis, D. Diaz, K. Gunasekaran, K. Henne, Joseph W. Lewcock, P. Sanchez, M. Troyer, Jeffrey M Harris, K. Scearce-Levie, L. Shan, R. Watts, R. Thorne, Anastasia G. Henry, Mihalis S. Kariolis

{"title":"Molecular architecture determines brain delivery of a transferrin receptor–targeted lysosomal enzyme","authors":"A. Arguello, Cathal S. Mahon, M. E. Calvert, D. Chan, J. Dugas, Michelle E Pizzo, Elliot R. Thomsen, Roni Chau, Lorna A Damo, Joseph Duque, Meng Fang, T. Giese, Do Jin Kim, Nicholas Liang, Hoang N. Nguyen, Hilda Solanoy, Buyankhishig Tsogtbaatar, J. Ullman, Junhua Wang, M. Dennis, D. Diaz, K. Gunasekaran, K. Henne, Joseph W. Lewcock, P. Sanchez, M. Troyer, Jeffrey M Harris, K. Scearce-Levie, L. Shan, R. Watts, R. Thorne, Anastasia G. Henry, Mihalis S. Kariolis","doi":"10.1084/jem.20211057","DOIUrl":"https://doi.org/10.1084/jem.20211057","url":null,"abstract":"Delivery of biotherapeutics across the blood-brain barrier (BBB) is a challenge. Many approaches fuse biotherapeutics to platforms that bind the transferrin receptor (TfR), a brain endothelial cell target, to facilitate receptor-mediated transcytosis across the BBB. Here, we characterized the pharmacological behavior of two distinct TfR-targeted platforms fused to iduronate 2-sulfatase (IDS), a lysosomal enzyme deficient in mucopolysaccharidosis type II (MPS II), and compared the relative brain exposures and functional activities of both approaches in mouse models. IDS fused to a moderate-affinity, monovalent TfR binding enzyme transport vehicle (ETV:IDS) resulted in widespread brain exposure, internalization by parenchymal cells, and significant substrate reduction in the CNS of an MPS II mouse model. In contrast, IDS fused to a standard high-affinity bivalent antibody (IgG:IDS) resulted in lower brain uptake, limited biodistribution beyond brain endothelial cells, and reduced brain substrate reduction. These results highlight important features likely to impact the clinical development of TfR-targeting platforms in MPS II and potentially other CNS diseases. Summary Brain delivery, biodistribution and pharmacodynamics of a lysosomal enzyme fused to a moderate-affinity transferrin receptor-directed blood-brain barrier enzyme transport vehicle are superior to a traditional high-affinity anti-TfR monoclonal antibody fusion.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2021-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82308808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 22

Immune checkpoint inhibitors 免疫检查点抑制剂

The Tokushima journal of experimental medicine Pub Date : 2021-02-16 DOI: 10.1007/s40278-017-37902-z

G. Kroemer, L. Zitvogel

引用次数: 0

The human fetal thymus generates invariant effector γδ T cells. 人胎儿胸腺产生不变的效应γδ T细胞。

The Tokushima journal of experimental medicine Pub Date : 2020-03-02 DOI: 10.1084/jem.20190580

Paola Tieppo, Maria Papadopoulou, Deborah Gatti, Naomi McGovern, Jerry K Y Chan, Françoise Gosselin, Glenn Goetgeluk, Karin Weening, Ling Ma, Nicolas Dauby, Alexandra Cogan, Catherine Donner, Florent Ginhoux, Bart Vandekerckhove, David Vermijlen

{"title":"The human fetal thymus generates invariant effector γδ T cells.","authors":"Paola Tieppo, Maria Papadopoulou, Deborah Gatti, Naomi McGovern, Jerry K Y Chan, Françoise Gosselin, Glenn Goetgeluk, Karin Weening, Ling Ma, Nicolas Dauby, Alexandra Cogan, Catherine Donner, Florent Ginhoux, Bart Vandekerckhove, David Vermijlen","doi":"10.1084/jem.20190580","DOIUrl":"10.1084/jem.20190580","url":null,"abstract":"In the mouse thymus, invariant γδ T cells are generated at well-defined times during development and acquire effector functions before exiting the thymus. However, whether such thymic programming and age-dependent generation of invariant γδ T cells occur in humans is not known. Here we found that, unlike postnatal γδ thymocytes, human fetal γδ thymocytes were functionally programmed (e.g., IFNγ, granzymes) and expressed low levels of terminal deoxynucleotidyl transferase (TdT). This low level of TdT resulted in a low number of N nucleotide insertions in the complementarity-determining region-3 (CDR3) of their TCR repertoire, allowing the usage of short homology repeats within the germline-encoded VDJ segments to generate invariant/public cytomegalovirus-reactive CDR3 sequences (TRGV8-TRJP1-CATWDTTGWFKIF, TRDV2-TRDD3-CACDTGGY, and TRDV1-TRDD3-CALGELGD). Furthermore, both the generation of invariant TCRs and the intrathymic acquisition of effector functions were due to an intrinsic property of fetal hematopoietic stem and precursor cells (HSPCs) caused by high expression of the RNA-binding protein Lin28b. In conclusion, our data indicate that the human fetal thymus generates, in an HSPC/Lin28b-dependent manner, invariant γδ T cells with programmed effector functions.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"308 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7062527/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79911390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

B cell tolerance and antibody production to the celiac disease autoantigen transglutaminase 2. B细胞对乳糜泻自身抗原转谷氨酰胺酶2的耐受性和抗体产生。

The Tokushima journal of experimental medicine Pub Date : 2020-02-03 DOI: 10.1084/jem.20190860

M Fleur du Pré, Jana Blazevski, Alisa E Dewan, Jorunn Stamnaes, Chakravarthi Kanduri, Geir Kjetil Sandve, Marie K Johannesen, Christian B Lindstad, Kathrin Hnida, Lars Fugger, Gerry Melino, Shuo-Wang Qiao, Ludvig M Sollid

{"title":"B cell tolerance and antibody production to the celiac disease autoantigen transglutaminase 2.","authors":"M Fleur du Pré, Jana Blazevski, Alisa E Dewan, Jorunn Stamnaes, Chakravarthi Kanduri, Geir Kjetil Sandve, Marie K Johannesen, Christian B Lindstad, Kathrin Hnida, Lars Fugger, Gerry Melino, Shuo-Wang Qiao, Ludvig M Sollid","doi":"10.1084/jem.20190860","DOIUrl":"10.1084/jem.20190860","url":null,"abstract":"Autoantibodies to transglutaminase 2 (TG2) are hallmarks of celiac disease. To address B cell tolerance and autoantibody formation to TG2, we generated immunoglobulin knock-in (Ig KI) mice that express a prototypical celiac patient-derived anti-TG2 B cell receptor equally reactive to human and mouse TG2. We studied B cell development in the presence/absence of autoantigen by crossing the Ig KI mice to Tgm2-/- mice. Autoreactive B cells in Tgm2+/+ mice were indistinguishable from their naive counterparts in Tgm2-/- mice with no signs of clonal deletion, receptor editing, or B cell anergy. The autoreactive B cells appeared ignorant to their antigen, and they produced autoantibodies when provided T cell help. The findings lend credence to a model of celiac disease where gluten-reactive T cells provide help to autoreactive TG2-specific B cells by involvement of gluten-TG2 complexes, and they outline a general mechanism of autoimmunity with autoantibodies being produced by ignorant B cells on provision of T cell help.","PeriodicalId":23015,"journal":{"name":"The Tokushima journal of experimental medicine","volume":"130 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041703/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79588894","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Biology and therapeutic potential of interleukin-10. 白细胞介素-10的生物学和治疗潜力。

The Tokushima journal of experimental medicine Pub Date : 2020-01-06 DOI: 10.1084/jem.20190418

Margarida Saraiva, Paulo Vieira, Anne O'Garra

引用次数: 0