Science Immunology最新文献

Palmitoylation of TIM-3 promotes immune exhaustion and restrains antitumor immunity TIM-3 的棕榈酰化促进免疫衰竭并抑制抗肿瘤免疫力

IF 17.6 1区医学

Science Immunology Pub Date : 2024-11-15 DOI: 10.1126/sciimmunol.adp7302

Zhaoying Zhang, Caiyue Ren, Rong Xiao, Shuaiya Ma, Huimin Liu, Yutong Dou, Yuchen Fan, Shuo Wang, Peng Zhan, Chengjiang Gao, Xuetian Yue, Chunyang Li, Lifen Gao, Xiaohong Liang, Zhuanchang Wu, Chunhong Ma

{"title":"Palmitoylation of TIM-3 promotes immune exhaustion and restrains antitumor immunity","authors":"Zhaoying Zhang, Caiyue Ren, Rong Xiao, Shuaiya Ma, Huimin Liu, Yutong Dou, Yuchen Fan, Shuo Wang, Peng Zhan, Chengjiang Gao, Xuetian Yue, Chunyang Li, Lifen Gao, Xiaohong Liang, Zhuanchang Wu, Chunhong Ma","doi":"10.1126/sciimmunol.adp7302","DOIUrl":"10.1126/sciimmunol.adp7302","url":null,"abstract":"<div >T cell immunoglobulin and mucin domain–containing protein 3 (TIM-3) is an immune checkpoint that has critical roles in immune exhaustion. However, little is known about the mechanisms that regulate TIM-3 surface expression and turnover. Here, we report that human TIM-3 is palmitoylated by the palmitoyltransferase DHHC9 at residue cysteine 296 (Cys<sup>296</sup>). Palmitoylation stabilized TIM-3 by preventing binding to E3 ubiquitin ligase HRD1, thereby suppressing its polyubiquitination and degradation. DHHC9 knockdown attenuated chimeric antigen receptor T (CAR-T) cell exhaustion, and a peptidic inhibitor of TIM-3 palmitoylation accelerated TIM-3 degradation and enhanced antitumor immunity mediated by CAR-T cells and natural killer (NK) cells. In hepatocellular carcinoma, DHHC9 expression correlated with TIM-3 expression in CD8<sup>+</sup> T cells and NK cells, and high DHHC9 expression was associated with shorter survival in patients with high TIM-3. These findings demonstrate that palmitoylation of TIM-3 catalyzed by DHHC9 promotes its stability, resulting in immune exhaustion and impaired antitumor immunity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 101","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adp7302","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A tetraspecific engager armed with a non-alpha IL-2 variant harnesses natural killer cells against B cell non-Hodgkin lymphoma 用非αIL-2变体武装的四特异性捕获器利用自然杀伤细胞对抗B细胞非霍奇金淋巴瘤

IF 17.6 1区医学

Science Immunology Pub Date : 2024-11-15 DOI: 10.1126/sciimmunol.adp3720

Olivier Demaria, Guillaume Habif, Marie Vetizou, Laurent Gauthier, Romain Remark, Laura Chiossone, Constance Vagne, Lucas Rebuffet, Rachel Courtois, Caroline Denis, François Le Floch, Marianna Muller, Mathilde Girard-Madoux, Séverine Augier, Julie Lopez, Barbara Carrette, Aurélie Maguer, Jean-Baptiste Vallier, Gwendoline Grondin, William Baron, Justine Galluso, Nadia Yessaad, Marilyn Giordano, Léa Simon, Fabien Chanuc, Audrey Blanchard Alvarez, Ivan Perrot, Cécile Bonnafous, Agnès Represa, Benjamin Rossi, Ariane Morel, Yannis Morel, Carine Paturel, Eric Vivier

{"title":"A tetraspecific engager armed with a non-alpha IL-2 variant harnesses natural killer cells against B cell non-Hodgkin lymphoma","authors":"Olivier Demaria, Guillaume Habif, Marie Vetizou, Laurent Gauthier, Romain Remark, Laura Chiossone, Constance Vagne, Lucas Rebuffet, Rachel Courtois, Caroline Denis, François Le Floch, Marianna Muller, Mathilde Girard-Madoux, Séverine Augier, Julie Lopez, Barbara Carrette, Aurélie Maguer, Jean-Baptiste Vallier, Gwendoline Grondin, William Baron, Justine Galluso, Nadia Yessaad, Marilyn Giordano, Léa Simon, Fabien Chanuc, Audrey Blanchard Alvarez, Ivan Perrot, Cécile Bonnafous, Agnès Represa, Benjamin Rossi, Ariane Morel, Yannis Morel, Carine Paturel, Eric Vivier","doi":"10.1126/sciimmunol.adp3720","DOIUrl":"10.1126/sciimmunol.adp3720","url":null,"abstract":"<div >NK cells offer a promising alternative to T cell therapies in cancer. We evaluated IPH6501, a clinical-stage, tetraspecific NK cell engager (NKCE) armed with a non-alpha IL-2 variant (IL-2v), which targets CD20 and was developed for treating B cell non-Hodgkin lymphoma (B-NHL). CD20-NKCE-IL2v boosts NK cell proliferation and cytotoxicity, showing activity against a range of B-NHL cell lines, including those with low CD20 density. Whereas it presented reduced toxicities compared with those commonly associated with T cell therapies, CD20-NKCE-IL2v showed greater killing efficacy over a T cell engager targeting CD20 in in vitro preclinical models. CD20-NKCE-IL2v also increased the cell surface expression of NK cell–activating receptors, leading to activity against CD20-negative tumor cells. In vivo studies in nonhuman primates and tumor mouse models further validated its efficacy and revealed that CD20-NKCE-IL2v induces peripheral NK cell homing at the tumor site. CD20-NKCE-IL2v emerges as a potential alternative in the treatment landscape of B-NHL.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 101","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adp3720","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A B cell screen against endogenous retroviruses identifies glycan-reactive IgM that recognizes a broad array of enveloped viruses 针对内源性逆转录病毒的 B 细胞筛选发现了能识别多种包膜病毒的糖反应 IgM

IF 17.6 1区医学

Science Immunology Pub Date : 2024-11-08 DOI: 10.1126/sciimmunol.add6608

Yexin Yang, Rebecca S. Treger, Juan Hernandez-Bird, Peiwen Lu, Tianyang Mao, Akiko Iwasaki

{"title":"A B cell screen against endogenous retroviruses identifies glycan-reactive IgM that recognizes a broad array of enveloped viruses","authors":"Yexin Yang, Rebecca S. Treger, Juan Hernandez-Bird, Peiwen Lu, Tianyang Mao, Akiko Iwasaki","doi":"10.1126/sciimmunol.add6608","DOIUrl":"10.1126/sciimmunol.add6608","url":null,"abstract":"<div >Endogenous retroviruses (ERVs), comprising a substantial portion of the vertebrate genome, are remnants of ancient genetic invaders. ERVs with near-intact coding potential reactivate in B cell–deficient mice. To study how B cells contribute to host anti-ERV immunity, we used an antigen-baiting strategy to enrich B cells reactive to ERV surface antigens. We identified ERV-reactive B-1 cells expressing germline-encoded natural IgM antibodies in naïve mice, the level of which further increases upon innate immune sensor stimulation. B cell receptor repertoire profiling of ERV-reactive B-1 cells revealed increased usage of the <i>Igh</i> V<sub>H</sub> gene that gives rise to glycan-specific antibodies targeting terminal <i>N</i>-acetylglucosamine moieties on ERV glycoproteins, which further engage the complement pathway to mediate anti-ERV responses. These same antibodies also recognize glycoproteins of other enveloped viruses but not self-proteins. These results reveal an innate antiviral mechanism of germline-encoded antibodies with broad reactivity to enveloped viruses, which constitutes a natural antibody repertoire capable of preventing the emergence of infectious ERVs.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 101","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.add6608","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Macrophage LRRK2 hyperactivity impairs autophagy and induces Paneth cell dysfunction 巨噬细胞 LRRK2 活性亢进会损害自噬作用并诱发潘氏细胞功能障碍

IF 17.6 1区医学

Science Immunology Pub Date : 2024-11-08 DOI: 10.1126/sciimmunol.adi7907

Shengxiang Sun, Miki Hodel, Xiang Wang, Javier De Vicente, Talin Haritunians, Anketse Debebe, Chen-Ting Hung, Changqing Ma, Atika Malique, Hoang N. Nguyen, Maayan Agam, Michael T. Maloney, Marisa S. Goo, Jillian H. Kluss, Richa Mishra, Jennifer Frein, Amanda Foster, Samuel Ballentine, Uday Pandey, Justin Kern, Shaohong Yang, Emebet Mengesha, Iyshwarya Balasubramanian, Annie Arguello, Anthony A. Estrada, Nan Gao, Inga Peter, Dermot P. B. McGovern, Anastasia G. Henry, Thaddeus S. Stappenbeck, Ta-Chiang Liu

{"title":"Macrophage LRRK2 hyperactivity impairs autophagy and induces Paneth cell dysfunction","authors":"Shengxiang Sun, Miki Hodel, Xiang Wang, Javier De Vicente, Talin Haritunians, Anketse Debebe, Chen-Ting Hung, Changqing Ma, Atika Malique, Hoang N. Nguyen, Maayan Agam, Michael T. Maloney, Marisa S. Goo, Jillian H. Kluss, Richa Mishra, Jennifer Frein, Amanda Foster, Samuel Ballentine, Uday Pandey, Justin Kern, Shaohong Yang, Emebet Mengesha, Iyshwarya Balasubramanian, Annie Arguello, Anthony A. Estrada, Nan Gao, Inga Peter, Dermot P. B. McGovern, Anastasia G. Henry, Thaddeus S. Stappenbeck, Ta-Chiang Liu","doi":"10.1126/sciimmunol.adi7907","DOIUrl":"10.1126/sciimmunol.adi7907","url":null,"abstract":"<div ><i>LRRK2</i> polymorphisms (G2019S/N2081D) that increase susceptibility to Parkinson’s disease and Crohn’s disease (CD) lead to LRRK2 kinase hyperactivity and suppress autophagy. This connection suggests that LRRK2 kinase inhibition, a therapeutic strategy being explored for Parkinson’s disease, may also benefit patients with CD. Paneth cell homeostasis is tightly regulated by autophagy, and their dysfunction is a precursor to gut inflammation in CD. Here, we found that patients with CD and mice carrying hyperactive <i>LRRK2</i> polymorphisms developed Paneth cell dysfunction. We also found that LRRK2 kinase can be activated in the context of interactions between genes (genetic autophagy deficiency) and the environment (cigarette smoking). Unexpectedly, lamina propria immune cells were the main intestinal cell types that express LRRK2, instead of Paneth cells as previously suggested. We showed that LRRK2-mediated pro-inflammatory cytokine release from phagocytes impaired Paneth cell function, which was rescued by LRRK2 kinase inhibition through activation of autophagy. Together, these data suggest that LRRK2 kinase inhibitors maintain Paneth cell homeostasis by restoring autophagy and may represent a therapeutic strategy for CD.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 101","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596856","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Monocytes and their doppelgängers: An immunological crossroads 单核细胞及其二倍体：免疫学的十字路口

IF 17.6 1区医学

Science Immunology Pub Date : 2024-11-01 DOI: 10.1126/sciimmunol.adr6672

Alexander Mildner, Simon Yona

引用次数: 0

Kupffer cell reverse migration into the liver sinusoids mitigates neonatal sepsis and meningitis 库普弗细胞逆向迁移到肝窦可减轻新生儿败血症和脑膜炎的病情

IF 17.6 1区医学

Science Immunology Pub Date : 2024-11-01 DOI: 10.1126/sciimmunol.adq9704

Bruna Araujo David, Jawairia Atif, Fernanda Vargas e Silva Castanheira, Tamanna Yasmin, Adrien Guillot, Yeni Ait Ahmed, Moritz Peiseler, Josefien W. Hommes, Lilian Salm, Marie-Anne Brundler, Bas G. J. Surewaard, Wael Elhenawy, Sonya MacParland, Florent Ginhoux, Kathy McCoy, Paul Kubes

{"title":"Kupffer cell reverse migration into the liver sinusoids mitigates neonatal sepsis and meningitis","authors":"Bruna Araujo David, Jawairia Atif, Fernanda Vargas e Silva Castanheira, Tamanna Yasmin, Adrien Guillot, Yeni Ait Ahmed, Moritz Peiseler, Josefien W. Hommes, Lilian Salm, Marie-Anne Brundler, Bas G. J. Surewaard, Wael Elhenawy, Sonya MacParland, Florent Ginhoux, Kathy McCoy, Paul Kubes","doi":"10.1126/sciimmunol.adq9704","DOIUrl":"10.1126/sciimmunol.adq9704","url":null,"abstract":"<div >In adults, liver-resident macrophages, or Kupffer cells (KCs), reside in the sinusoids and sterilize circulating blood by capturing rapidly flowing microbes. We developed quantitative intravital imaging of 1-day-old mice combined with transcriptomics, genetic manipulation, and in vivo infection assays to interrogate increased susceptibility of newborns to bloodstream infections. Whereas 1-day-old KCs were better at catching <i>Escherichia coli</i> in vitro, we uncovered a critical 1-week window postpartum when KCs have limited access to blood and must translocate from liver parenchyma into the sinusoids. KC migration was independent of the microbiome but depended on macrophage migration inhibitory factor, its receptor CD74, and the adhesion molecule CD44. On the basis of our findings, we propose a model of progenitor macrophage seeding of the liver sinusoids via a reverse transmigration process from liver parenchyma. These results also illustrate the importance of developing newborn mouse models to understand newborn immunity and disease.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 101","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adq9704","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562161","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

CAR-ving away OX40L with engineered Tregs 利用工程化 Tregs 清除 OX40L。

IF 17.6 1区医学

Science Immunology Pub Date : 2024-11-01 DOI: 10.1126/sciimmunol.adu0983

Jonathan S. Maltzman

引用次数: 0

The pore-forming apolipoprotein APOL7C drives phagosomal rupture and antigen cross-presentation by dendritic cells 形成孔隙的载脂蛋白 APOL7C 驱动吞噬体破裂和树突状细胞的抗原交叉呈递

IF 17.6 1区医学

Science Immunology Pub Date : 2024-11-01 DOI: 10.1126/sciimmunol.adn2168

Gerone A. Gonzales, Song Huang, Liam Wilkinson, Jenny A. Nguyen, Saif Sikdar, Cécile Piot, Victor Naumenko, Jahanara Rajwani, Cassandra M. Wood, Irene Dinh, Melanie Moore, Eymi Cedeño, Neil McKenna, Maria J. Polyak, Sara Amidian, Vincent Ebacher, Nicole L. Rosin, Matheus B. Carneiro, Bas Surewaard, Nathan C. Peters, Christopher H. Mody, Jeff Biernaskie, Robin M. Yates, Douglas J. Mahoney, Johnathan Canton

{"title":"The pore-forming apolipoprotein APOL7C drives phagosomal rupture and antigen cross-presentation by dendritic cells","authors":"Gerone A. Gonzales, Song Huang, Liam Wilkinson, Jenny A. Nguyen, Saif Sikdar, Cécile Piot, Victor Naumenko, Jahanara Rajwani, Cassandra M. Wood, Irene Dinh, Melanie Moore, Eymi Cedeño, Neil McKenna, Maria J. Polyak, Sara Amidian, Vincent Ebacher, Nicole L. Rosin, Matheus B. Carneiro, Bas Surewaard, Nathan C. Peters, Christopher H. Mody, Jeff Biernaskie, Robin M. Yates, Douglas J. Mahoney, Johnathan Canton","doi":"10.1126/sciimmunol.adn2168","DOIUrl":"10.1126/sciimmunol.adn2168","url":null,"abstract":"<div >Conventional dendritic cells (cDCs) generate protective cytotoxic T lymphocyte (CTL) responses against extracellular pathogens and tumors. This is achieved through a process known as cross-presentation (XP), and, despite its biological importance, the mechanism(s) driving XP remains unclear. Here, we show that a cDC-specific pore-forming protein called apolipoprotein L 7C (APOL7C) is up-regulated in response to innate immune stimuli and is recruited to phagosomes. Association of APOL7C with phagosomes led to phagosomal rupture and escape of engulfed antigens to the cytosol, where they could be processed via the endogenous MHC class I antigen processing pathway. Accordingly, mice deficient in APOL7C did not efficiently prime CD8<sup>+</sup> T cells in response to immunization with bead-bound and cell-associated antigens. Together, our data indicate the presence of dedicated apolipoproteins that mediate the delivery of phagocytosed proteins to the cytosol of activated cDCs to facilitate XP.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 101","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142562144","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

TAM-ing the beast with IL-34 blockade 用 IL-34 阻断 TAM--野兽

IF 17.6 1区医学

Science Immunology Pub Date : 2024-11-01 DOI: 10.1126/sciimmunol.adu0981

Aron Gyorgypal, Robert M. Anthony

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Orientation-dependent CD45 inhibition with viral and engineered ligands 利用病毒配体和工程配体抑制定向依赖性 CD45

IF 17.6 1区医学

Science Immunology Pub Date : 2024-10-25 DOI: 10.1126/sciimmunol.adp0707

Marta T. Borowska, Liu D. Liu, Nathanael A. Caveney, Kevin M. Jude, Won-Ju Kim, Takeya Masubuchi, Enfu Hui, Robbie G. Majzner, K. Christopher Garcia

引用次数: 0