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 (Cys296). 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+ 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.
{"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}
Pub Date : 2024-11-15DOI: 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
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.
在癌症治疗中，NK细胞为T细胞疗法提供了一种前景广阔的替代疗法。我们对 IPH6501 进行了评估，它是一种处于临床阶段的四特异性 NK 细胞吞噬剂（NKCE），带有非α IL-2 变体（IL-2v），靶向 CD20，用于治疗 B 细胞非霍奇金淋巴瘤（B-NHL）。CD20-NKCE-IL2v 可促进 NK 细胞的增殖和细胞毒性，对一系列 B-NHL 细胞系（包括 CD20 密度低的细胞系）具有活性。与通常的 T 细胞疗法相比，CD20-NKCE-IL2v 的毒性更低，在体外临床前模型中，CD20-NKCE-IL2v 比以 CD20 为靶点的 T 细胞诱导剂具有更强的杀伤力。CD20-NKCE-IL2v 还能增加细胞表面 NK 细胞激活受体的表达，从而提高对 CD20 阴性肿瘤细胞的活性。在非人灵长类动物和肿瘤小鼠模型中进行的体内研究进一步验证了CD20-NKCE-IL2v的疗效，并发现CD20-NKCE-IL2v能诱导外周NK细胞在肿瘤部位归巢。CD20-NKCE-IL2v 成为治疗 B-NHL 的潜在替代疗法。
{"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}
Pub Date : 2024-11-08DOI: 10.1126/sciimmunol.add6608
Yexin Yang, Rebecca S. Treger, Juan Hernandez-Bird, Peiwen Lu, Tianyang Mao, Akiko Iwasaki
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 Igh VH gene that gives rise to glycan-specific antibodies targeting terminal N-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.
内源性逆转录病毒（ERV）占脊椎动物基因组的很大一部分，是古老基因入侵者的残余。具有近乎完整编码潜能的ERV会在B细胞缺陷小鼠体内重新激活。为了研究 B 细胞如何促进宿主的抗逆转录病毒免疫，我们使用了一种抗原诱饵策略来富集对 ERV 表面抗原有反应的 B 细胞。我们在天真小鼠体内发现了表达种系编码天然 IgM 抗体的 ERV 反应性 B-1 细胞，其水平在先天性免疫传感器刺激下进一步提高。ERV反应性B-1细胞的B细胞受体谱分析显示，Igh V H基因的使用率增加，从而产生了针对ERV糖蛋白末端N-乙酰葡糖胺分子的糖特异性抗体，这些抗体进一步参与补体途径，介导抗ERV反应。这些抗体还能识别其他包膜病毒的糖蛋白，但不能识别自身蛋白。这些结果揭示了一种先天性抗病毒机制，即种系编码的抗体对包膜病毒具有广泛的反应性，这种抗体构成了一种天然的抗体库，能够防止传染性 ERV 的出现。
{"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}
Pub Date : 2024-11-08DOI: 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
LRRK2 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 LRRK2 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.
{"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}
Pub Date : 2024-11-01DOI: 10.1126/sciimmunol.adr6672
Alexander Mildner, Simon Yona
Identity confusion has emerged in the field of monocyte research with the identification of monocyte-like “doppelgänger” populations that exhibit phenotypical traits of classical monocytes but seem to vary in their origin, function, or migration behavior.
{"title":"Monocytes and their doppelgängers: An immunological crossroads","authors":"Alexander Mildner, Simon Yona","doi":"10.1126/sciimmunol.adr6672","DOIUrl":"10.1126/sciimmunol.adr6672","url":null,"abstract":"<div >Identity confusion has emerged in the field of monocyte research with the identification of monocyte-like “doppelgänger” populations that exhibit phenotypical traits of classical monocytes but seem to vary in their origin, function, or migration behavior.</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":"142562142","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}
Pub Date : 2024-11-01DOI: 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
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 Escherichia coli 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.
{"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}
Pub Date : 2024-11-01DOI: 10.1126/sciimmunol.adu0983
Jonathan S. Maltzman
OX40L–CAR-Tregs show promise for treating autoimmunity and transplantation rejection.
OX40L-CAR-Tregs有望治疗自身免疫和移植排斥反应。
{"title":"CAR-ving away OX40L with engineered Tregs","authors":"Jonathan S. Maltzman","doi":"10.1126/sciimmunol.adu0983","DOIUrl":"10.1126/sciimmunol.adu0983","url":null,"abstract":"<div >OX40L–CAR-T<sub>regs</sub> show promise for treating autoimmunity and transplantation rejection.</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":"142562836","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}
Pub Date : 2024-11-01DOI: 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
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+ 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.
传统的树突状细胞（cDCs）能产生针对细胞外病原体和肿瘤的保护性细胞毒性 T 淋巴细胞（CTL）反应。尽管XP具有重要的生物学意义，但其驱动机制仍不清楚。在这里，我们发现一种叫做脂蛋白 L 7C （APOL7C）的 cDC 特异性孔形成蛋白在先天性免疫刺激下上调，并被招募到吞噬体中。APOL7C 与吞噬体的结合导致吞噬体破裂，被吞噬的抗原逃逸到细胞膜，在细胞膜上通过内源性 MHC I 类抗原处理途径进行处理。因此，缺乏 APOL7C 的小鼠在对珠状抗原和细胞相关抗原进行免疫时不能有效地激发 CD8 + T 细胞。总之，我们的数据表明，存在一种专用的脂蛋白，它能介导将吞噬的蛋白质输送到活化的 cDCs 的细胞质中，从而促进 XP 的产生。
{"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}
Pub Date : 2024-11-01DOI: 10.1126/sciimmunol.adu0981
Aron Gyorgypal, Robert M. Anthony
TP53 mutation triggers IL-34 secretion by cancer stem cells, reprogramming macrophages to suppress T cells and promote tumor immune escape.
TP53突变引发癌症干细胞分泌IL-34，使巨噬细胞重新编程，从而抑制T细胞，促进肿瘤免疫逃逸。
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Pub Date : 2024-10-25DOI: 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
CD45 is a cell surface phosphatase that shapes the T cell receptor signaling threshold but does not have a known ligand. A family of adenovirus proteins, including E3/49K, exploits CD45 to evade immunity by binding to the extracellular domain of CD45, resulting in the suppression of T cell signaling. We determined the cryo-EM structure of this complex and found that the E3/49K protein is composed of three immunoglobulin domains assembled as “beads on a string” that compel CD45 into a closely abutted dimer by cross-linking the CD45 D3 domain, leading to steric inhibition of its intracellular phosphatase activity. Inspired by the E3/49K mechanism, we engineered CD45 surrogate ligands that can fine-tune T cell activation by dimerizing CD45 into different orientations and proximities. The adenovirus E3/49K protein has taught us that, despite a lack of a known ligand, CD45 activity can be modulated by extracellular dimerizing ligands that perturb its phosphatase activity and alter T cell responses.
CD45 是一种细胞表面磷酸酶，可形成 T 细胞受体信号阈值，但没有已知的配体。包括 E3/49K 在内的一系列腺病毒蛋白通过与 CD45 的细胞外结构域结合，抑制 T 细胞信号传导，从而利用 CD45 逃避免疫。我们测定了这一复合物的低温电子显微镜结构，发现 E3/49K 蛋白由三个免疫球蛋白结构域组成，它们像 "串珠 "一样组装在一起，通过交联 CD45 D3 结构域迫使 CD45 变成一个紧密相连的二聚体，从而导致其细胞内磷酸酶活性受到立体抑制。受 E3/49K 机制的启发，我们设计出了 CD45 替代配体，它们可以通过将 CD45 二聚为不同的方向和接近度来微调 T 细胞的活化。腺病毒 E3/49K 蛋白告诉我们，尽管缺乏已知的配体，但 CD45 的活性可以通过细胞外二聚配体来调节，从而扰乱其磷酸酶活性并改变 T 细胞的反应。
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