Pub Date : 2024-08-05Epub Date: 2024-07-01DOI: 10.1084/jem.20240849
Cindy S Ma, Stuart G Tangye
Germline activating mutations in STAT3 cause a multi-systemic autoimmune and autoinflammatory condition. By studying a mouse model, Toth et al. (https://doi.org/10.1084/jem.20232091) propose a role for dysregulated IL-22 production by Th17 cells in causing some aspects of immune-mediated skin inflammation in human STAT3 GOF syndrome.
{"title":"STAT3 gain of function: Too much of a good thing in the skin!","authors":"Cindy S Ma, Stuart G Tangye","doi":"10.1084/jem.20240849","DOIUrl":"10.1084/jem.20240849","url":null,"abstract":"<p><p>Germline activating mutations in STAT3 cause a multi-systemic autoimmune and autoinflammatory condition. By studying a mouse model, Toth et al. (https://doi.org/10.1084/jem.20232091) propose a role for dysregulated IL-22 production by Th17 cells in causing some aspects of immune-mediated skin inflammation in human STAT3 GOF syndrome.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-08-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11215521/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141468423","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 : 2024-07-01Epub Date: 2024-05-07DOI: 10.1084/jem.20240582
Leen Hermans, Timothy E O'Sullivan
A method to precisely determine which cells respond to chemokines in vivo is currently lacking. A novel class of dual fluorescence reporter mice could help identify cells that produce and/or sense a given chemokine in vitro and in vivo (Rodrigo et al. 2024. J. Exp. Med.https://doi.org/10.1084/jem.20231814).
{"title":"Send it, receive it, quick erase it: A mouse model to decipher chemokine communication.","authors":"Leen Hermans, Timothy E O'Sullivan","doi":"10.1084/jem.20240582","DOIUrl":"10.1084/jem.20240582","url":null,"abstract":"<p><p>A method to precisely determine which cells respond to chemokines in vivo is currently lacking. A novel class of dual fluorescence reporter mice could help identify cells that produce and/or sense a given chemokine in vitro and in vivo (Rodrigo et al. 2024. J. Exp. Med.https://doi.org/10.1084/jem.20231814).</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":15.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11076807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140857541","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 : 2024-07-01Epub Date: 2024-05-09DOI: 10.1084/jem.20221122
Tamara Kögl, Hsin-Fang Chang, Julian Staniek, Samuel C C Chiang, Gudrun Thoulass, Jessica Lao, Kristoffer Weißert, Viviane Dettmer-Monaco, Kerstin Geiger, Paul T Manna, Vivien Beziat, Mana Momenilandi, Szu-Min Tu, Selina J Keppler, Varsha Pattu, Philipp Wolf, Laurence Kupferschmid, Stefan Tholen, Laura E Covill, Karolina Ebert, Tobias Straub, Miriam Groß, Ruth Gather, Helena Engel, Ulrich Salzer, Christoph Schell, Sarah Maier, Kai Lehmberg, Tatjana I Cornu, Hanspeter Pircher, Mohammad Shahrooei, Nima Parvaneh, Roland Elling, Marta Rizzi, Yenan T Bryceson, Stephan Ehl, Peter Aichele, Sandra Ammann
SYNTAXIN-11 (STX11) is a SNARE protein that mediates the fusion of cytotoxic granules with the plasma membrane at the immunological synapses of CD8 T or NK cells. Autosomal recessive inheritance of deleterious STX11 variants impairs cytotoxic granule exocytosis, causing familial hemophagocytic lymphohistiocytosis type 4 (FHL-4). In several FHL-4 patients, we also observed hypogammaglobulinemia, elevated frequencies of naive B cells, and increased double-negative DN2:DN1 B cell ratios, indicating a hitherto unrecognized role of STX11 in humoral immunity. Detailed analysis of Stx11-deficient mice revealed impaired CD4 T cell help for B cells, associated with disrupted germinal center formation, reduced isotype class switching, and low antibody avidity. Mechanistically, Stx11-/- CD4 T cells exhibit impaired membrane fusion leading to reduced CD107a and CD40L surface mobilization and diminished IL-2 and IL-10 secretion. Our findings highlight a critical role of STX11 in SNARE-mediated membrane trafficking and vesicle exocytosis in CD4 T cells, important for successful CD4 T cell-B cell interactions. Deficiency in STX11 impairs CD4 T cell-dependent B cell differentiation and humoral responses.
SYNTAXIN-11(STX11)是一种SNARE蛋白,在CD8 T细胞或NK细胞的免疫突触处介导细胞毒性颗粒与质膜的融合。STX11变体的常染色体隐性遗传会损害细胞毒性颗粒的外泌功能,从而导致家族性嗜血细胞淋巴组织细胞增多症4型(FHL-4)。在几例 FHL-4 患者中,我们还观察到了低丙种球蛋白血症、幼稚 B 细胞频率升高以及双阴性 DN2:DN1 B 细胞比率升高,这表明 STX11 在体液免疫中的作用迄今尚未得到承认。对 Stx11 基因缺陷小鼠的详细分析显示,CD4 T 细胞对 B 细胞的帮助受损,这与生殖中心的形成受到破坏、同种型类转换减少和抗体效价低有关。从机理上讲,Stx11-/-CD4 T细胞的膜融合功能受损,导致CD107a和CD40L表面动员能力下降,IL-2和IL-10分泌减少。我们的研究结果突显了 STX11 在 CD4 T 细胞 SNARE 介导的膜贩运和囊泡外排中的关键作用,这对 CD4 T 细胞与 B 细胞的成功互动非常重要。STX11的缺乏会损害CD4 T细胞依赖的B细胞分化和体液反应。
{"title":"Patients and mice with deficiency in the SNARE protein SYNTAXIN-11 have a secondary B cell defect.","authors":"Tamara Kögl, Hsin-Fang Chang, Julian Staniek, Samuel C C Chiang, Gudrun Thoulass, Jessica Lao, Kristoffer Weißert, Viviane Dettmer-Monaco, Kerstin Geiger, Paul T Manna, Vivien Beziat, Mana Momenilandi, Szu-Min Tu, Selina J Keppler, Varsha Pattu, Philipp Wolf, Laurence Kupferschmid, Stefan Tholen, Laura E Covill, Karolina Ebert, Tobias Straub, Miriam Groß, Ruth Gather, Helena Engel, Ulrich Salzer, Christoph Schell, Sarah Maier, Kai Lehmberg, Tatjana I Cornu, Hanspeter Pircher, Mohammad Shahrooei, Nima Parvaneh, Roland Elling, Marta Rizzi, Yenan T Bryceson, Stephan Ehl, Peter Aichele, Sandra Ammann","doi":"10.1084/jem.20221122","DOIUrl":"10.1084/jem.20221122","url":null,"abstract":"<p><p>SYNTAXIN-11 (STX11) is a SNARE protein that mediates the fusion of cytotoxic granules with the plasma membrane at the immunological synapses of CD8 T or NK cells. Autosomal recessive inheritance of deleterious STX11 variants impairs cytotoxic granule exocytosis, causing familial hemophagocytic lymphohistiocytosis type 4 (FHL-4). In several FHL-4 patients, we also observed hypogammaglobulinemia, elevated frequencies of naive B cells, and increased double-negative DN2:DN1 B cell ratios, indicating a hitherto unrecognized role of STX11 in humoral immunity. Detailed analysis of Stx11-deficient mice revealed impaired CD4 T cell help for B cells, associated with disrupted germinal center formation, reduced isotype class switching, and low antibody avidity. Mechanistically, Stx11-/- CD4 T cells exhibit impaired membrane fusion leading to reduced CD107a and CD40L surface mobilization and diminished IL-2 and IL-10 secretion. Our findings highlight a critical role of STX11 in SNARE-mediated membrane trafficking and vesicle exocytosis in CD4 T cells, important for successful CD4 T cell-B cell interactions. Deficiency in STX11 impairs CD4 T cell-dependent B cell differentiation and humoral responses.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":15.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11082451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140897958","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 : 2024-07-01Epub Date: 2024-06-13DOI: 10.1084/jem.20221721
Jonathan J Hodgins, John Abou-Hamad, Colin Edward O'Dwyer, Ash Hagerman, Edward Yakubovich, Christiano Tanese de Souza, Marie Marotel, Ariel Buchler, Saleh Fadel, Maria M Park, Claire Fong-McMaster, Mathieu F Crupi, Olivia Joan Makinson, Reem Kurdieh, Reza Rezaei, Harkirat Singh Dhillon, Carolina S Ilkow, John C Bell, Mary-Ellen Harper, Benjamin H Rotstein, Rebecca C Auer, Barbara C Vanderhyden, Luc A Sabourin, Marie-Claude Bourgeois-Daigneault, David P Cook, Michele Ardolino
While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced efficacy of oncolytic viruses in vitro and in vivo. Consistently, PD-L1 expression marked tumor explants from cancer patients that were best infected by oncolytic viruses. Mechanistically, PD-L1 promoted a metabolic shift characterized by enhanced glycolysis rate that resulted in increased lactate production. In turn, lactate inhibited type I IFN responses. In addition to adding mechanistic insight into PD-L1 intrinsic function, our results will also help guide the numerous ongoing efforts to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.
传统观点最初认为 PD-L1 是 PD-1 的惰性配体,但新出现的文献表明,PD-L1 在免疫细胞和癌细胞中具有细胞内在功能。与这些研究相一致,我们在此表明,通过细胞配体或激动抗体(包括临床上使用的抗体)与 PD-L1 结合,可有效抑制癌细胞中的 I 型干扰素通路。表达 PD-L1 的癌细胞中 I 型干扰素反应受阻,导致溶瘤病毒在体外和体内的疗效增强。一致的是,PD-L1 的表达标志着癌症患者的肿瘤外植体受到了溶瘤病毒的最佳感染。从机理上讲,PD-L1 促进了以糖酵解率提高为特征的新陈代谢转变,导致乳酸生成增加。反过来,乳酸盐又抑制了 I 型 IFN 反应。除了从机理上深入了解 PD-L1 的内在功能外,我们的研究结果还将有助于指导目前正在进行的将 PD-L1 抗体与溶瘤病毒疗法相结合的大量临床试验。
{"title":"PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I IFN pathway.","authors":"Jonathan J Hodgins, John Abou-Hamad, Colin Edward O'Dwyer, Ash Hagerman, Edward Yakubovich, Christiano Tanese de Souza, Marie Marotel, Ariel Buchler, Saleh Fadel, Maria M Park, Claire Fong-McMaster, Mathieu F Crupi, Olivia Joan Makinson, Reem Kurdieh, Reza Rezaei, Harkirat Singh Dhillon, Carolina S Ilkow, John C Bell, Mary-Ellen Harper, Benjamin H Rotstein, Rebecca C Auer, Barbara C Vanderhyden, Luc A Sabourin, Marie-Claude Bourgeois-Daigneault, David P Cook, Michele Ardolino","doi":"10.1084/jem.20221721","DOIUrl":"10.1084/jem.20221721","url":null,"abstract":"<p><p>While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1-expressing cancer cells resulted in enhanced efficacy of oncolytic viruses in vitro and in vivo. Consistently, PD-L1 expression marked tumor explants from cancer patients that were best infected by oncolytic viruses. Mechanistically, PD-L1 promoted a metabolic shift characterized by enhanced glycolysis rate that resulted in increased lactate production. In turn, lactate inhibited type I IFN responses. In addition to adding mechanistic insight into PD-L1 intrinsic function, our results will also help guide the numerous ongoing efforts to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11176258/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141310775","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 : 2024-07-01Epub Date: 2024-05-06DOI: 10.1084/jem.20240545
Adam J Rose, Sarah H Lockie
New studies (Tang et al. 2024. J. Exp. Med.https://doi.org/10.1084/jem.20231395) describe a liver stress pathway that is activated by certain chemotherapeutic drugs, which in turn induces a peptide hormone which partially mediates the lower food intake and body weight loss during chemotherapy treatment.
{"title":"Stress relief of chemo illness.","authors":"Adam J Rose, Sarah H Lockie","doi":"10.1084/jem.20240545","DOIUrl":"10.1084/jem.20240545","url":null,"abstract":"<p><p>New studies (Tang et al. 2024. J. Exp. Med.https://doi.org/10.1084/jem.20231395) describe a liver stress pathway that is activated by certain chemotherapeutic drugs, which in turn induces a peptide hormone which partially mediates the lower food intake and body weight loss during chemotherapy treatment.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":15.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11075642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140851109","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 : 2024-07-01Epub Date: 2024-06-11DOI: 10.1084/jem.20231442
Lingzi Hong, Tomasz Herjan, Xing Chen, Leah L Zagore, Katarzyna Bulek, Han Wang, Chi-Fu Jeffrey Yang, Donny D Licatalosi, Xiaoxia Li, Xiao Li
The IL-17 receptor adaptor molecule Act1, an RNA-binding protein, plays a critical role in IL-17-mediated cancer progression. Here, we report a novel mechanism of how IL-17/Act1 induces chemoresistance by modulating redox homeostasis through epitranscriptomic regulation of antioxidant RNA metabolism. Transcriptome-wide mapping of direct Act1-RNA interactions revealed that Act1 binds to the 5'UTR of antioxidant mRNAs and Wilms' tumor 1-associating protein (WTAP), a key regulator in m6A methyltransferase complex. Strikingly, Act1's binding sites are located in proximity to m6A modification sites, which allows Act1 to promote the recruitment of elF3G for cap-independent translation. Loss of Act1's RNA binding activity or Wtap knockdown abolished IL-17-induced m6A modification and translation of Wtap and antioxidant mRNAs, indicating a feedforward mechanism of the Act1-WTAP loop. We then developed antisense oligonucleotides (Wtap ASO) that specifically disrupt Act1's binding to Wtap mRNA, abolishing IL-17/Act1-WTAP-mediated antioxidant protein production during chemotherapy. Wtap ASO substantially increased the antitumor efficacy of cisplatin, demonstrating a potential therapeutic strategy for chemoresistance.
{"title":"Act1 drives chemoresistance via regulation of antioxidant RNA metabolism and redox homeostasis.","authors":"Lingzi Hong, Tomasz Herjan, Xing Chen, Leah L Zagore, Katarzyna Bulek, Han Wang, Chi-Fu Jeffrey Yang, Donny D Licatalosi, Xiaoxia Li, Xiao Li","doi":"10.1084/jem.20231442","DOIUrl":"10.1084/jem.20231442","url":null,"abstract":"<p><p>The IL-17 receptor adaptor molecule Act1, an RNA-binding protein, plays a critical role in IL-17-mediated cancer progression. Here, we report a novel mechanism of how IL-17/Act1 induces chemoresistance by modulating redox homeostasis through epitranscriptomic regulation of antioxidant RNA metabolism. Transcriptome-wide mapping of direct Act1-RNA interactions revealed that Act1 binds to the 5'UTR of antioxidant mRNAs and Wilms' tumor 1-associating protein (WTAP), a key regulator in m6A methyltransferase complex. Strikingly, Act1's binding sites are located in proximity to m6A modification sites, which allows Act1 to promote the recruitment of elF3G for cap-independent translation. Loss of Act1's RNA binding activity or Wtap knockdown abolished IL-17-induced m6A modification and translation of Wtap and antioxidant mRNAs, indicating a feedforward mechanism of the Act1-WTAP loop. We then developed antisense oligonucleotides (Wtap ASO) that specifically disrupt Act1's binding to Wtap mRNA, abolishing IL-17/Act1-WTAP-mediated antioxidant protein production during chemotherapy. Wtap ASO substantially increased the antitumor efficacy of cisplatin, demonstrating a potential therapeutic strategy for chemoresistance.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11167376/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141300724","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 : 2024-07-01Epub Date: 2024-06-11DOI: 10.1084/jem.20240842
Clarissa Campbell, Maja C Funk, Yuki Hattori, Wei Hu, Jana Jeschke, Colleen M Lau, Guang Sheng Ling, Siqi Liu, Verónica Lloréns-Rico, Elisa Nemes
{"title":"Women in STEM becoming independent: The journey to independence is an immensely gratifying odyssey.","authors":"Clarissa Campbell, Maja C Funk, Yuki Hattori, Wei Hu, Jana Jeschke, Colleen M Lau, Guang Sheng Ling, Siqi Liu, Verónica Lloréns-Rico, Elisa Nemes","doi":"10.1084/jem.20240842","DOIUrl":"10.1084/jem.20240842","url":null,"abstract":"","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":15.3,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11167372/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141300725","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 : 2024-07-01Epub Date: 2024-06-18DOI: 10.1084/jem.20240953
Lucie Van Emmenis
Linda-Gail Bekker is a professor, chief executive officer of the Desmond Tutu HIV Foundation, and director of the Desmond Tutu HIV Centre at the Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa. Her research interests include HIV treatment and prevention and tuberculosis, and she is active in developing community projects to promote education and research. We talked to Linda-Gail about her career, the importance of mentorship, and how rewarding it is to collaborate, mentor, and uplift other scientists.
{"title":"Linda-Gail Bekker: Mentorship is critical for anyone in STEM.","authors":"Lucie Van Emmenis","doi":"10.1084/jem.20240953","DOIUrl":"10.1084/jem.20240953","url":null,"abstract":"<p><p>Linda-Gail Bekker is a professor, chief executive officer of the Desmond Tutu HIV Foundation, and director of the Desmond Tutu HIV Centre at the Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa. Her research interests include HIV treatment and prevention and tuberculosis, and she is active in developing community projects to promote education and research. We talked to Linda-Gail about her career, the importance of mentorship, and how rewarding it is to collaborate, mentor, and uplift other scientists.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11187978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141419413","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 : 2024-07-01Epub Date: 2024-05-16DOI: 10.1084/jem.20231987
Ximena León-Lara, Alina S Fichtner, Maike Willers, Tao Yang, Katharina Schaper, Lennart Riemann, Jennifer Schöning, Anna Harms, Vicente Almeida, Anja Schimrock, Anika Janssen, Laura Ospina-Quintero, Constantin von Kaisenberg, Reinhold Förster, Matthias Eberl, Manuela F Richter, Sabine Pirr, Dorothee Viemann, Sarina Ravens
Preterm infants are at high risk of developing neonatal sepsis. γδ T cells are thought to be an important set of effector cells in neonates. Here, γδ T cells were investigated in a longitudinal cohort of preterm neonates using next-generation sequencing, flow cytometry, and functional assays. During the first year of life, the Vγ9Vδ2 T cell subset showed dynamic phenotypic changes and elevated levels of fetal-derived Vγ9Vδ2 T cells were evident in infants with sepsis. Single-cell transcriptomics identified HLA-DRhiCD83+ γδ T cells in neonatal sepsis, which expressed genes related to antigen presentation. In vitro assays showed that CD83 was expressed on activated Vγ9Vδ2 T cells in preterm and term neonates, but not in adults. In contrast, activation of adult Vγ9Vδ2 T cells enhanced CD86 expression, which was presumably the key receptor to induce CD4 T cell proliferation. Together, we provide a map of the maturation of γδ T cells after preterm birth and highlight their phenotypic diversity in infections.
早产儿患新生儿败血症的风险很高。γδT细胞被认为是新生儿中一组重要的效应细胞。在这里,我们使用新一代测序、流式细胞术和功能测试对早产新生儿纵向队列中的γδT细胞进行了研究。在新生儿出生后的第一年,Vγ9Vδ2 T细胞亚群表现出动态的表型变化,在患有败血症的婴儿中,胎儿来源的Vγ9Vδ2 T细胞水平明显升高。单细胞转录组学发现,新生儿败血症中的HLA-DRhiCD83+ γδ T细胞表达与抗原递呈相关的基因。体外试验显示,CD83 在早产儿和足月新生儿活化的 Vγ9Vδ2 T 细胞上表达,但在成人中没有表达。相反,激活成人 Vγ9Vδ2 T 细胞会增强 CD86 的表达,CD86 可能是诱导 CD4 T 细胞增殖的关键受体。总之,我们提供了早产后γδT细胞成熟的图谱,并强调了它们在感染中的表型多样性。
{"title":"γδ T cell profiling in a cohort of preterm infants reveals elevated frequencies of CD83+ γδ T cells in sepsis.","authors":"Ximena León-Lara, Alina S Fichtner, Maike Willers, Tao Yang, Katharina Schaper, Lennart Riemann, Jennifer Schöning, Anna Harms, Vicente Almeida, Anja Schimrock, Anika Janssen, Laura Ospina-Quintero, Constantin von Kaisenberg, Reinhold Förster, Matthias Eberl, Manuela F Richter, Sabine Pirr, Dorothee Viemann, Sarina Ravens","doi":"10.1084/jem.20231987","DOIUrl":"10.1084/jem.20231987","url":null,"abstract":"<p><p>Preterm infants are at high risk of developing neonatal sepsis. γδ T cells are thought to be an important set of effector cells in neonates. Here, γδ T cells were investigated in a longitudinal cohort of preterm neonates using next-generation sequencing, flow cytometry, and functional assays. During the first year of life, the Vγ9Vδ2 T cell subset showed dynamic phenotypic changes and elevated levels of fetal-derived Vγ9Vδ2 T cells were evident in infants with sepsis. Single-cell transcriptomics identified HLA-DRhiCD83+ γδ T cells in neonatal sepsis, which expressed genes related to antigen presentation. In vitro assays showed that CD83 was expressed on activated Vγ9Vδ2 T cells in preterm and term neonates, but not in adults. In contrast, activation of adult Vγ9Vδ2 T cells enhanced CD86 expression, which was presumably the key receptor to induce CD4 T cell proliferation. Together, we provide a map of the maturation of γδ T cells after preterm birth and highlight their phenotypic diversity in infections.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11098939/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140944456","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}