Pub Date : 2024-07-12DOI: 10.1126/sciimmunol.adm7908
Shuo Yang, Meijie Tian, Yulong Dai, Rong Wang, Shigehiro Yamada, Shengyong Feng, Yunyun Wang, Deepak Chhangani, Tiffany Ou, Wenle Li, Xuan Guo, Jennifer McAdow, Diego E. Rincon-Limas, Xin Yin, Wanbo Tai, Gong Cheng, Aaron Johnson
Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show nonneural symptoms including muscle pain and muscle fatigue. The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood. We developed multiple models to investigate the impact of CNS stressors on motor function and found that Escherichia coli infections and SARS-CoV-2 protein expression caused reactive oxygen species (ROS) to accumulate in the brain. ROS induced expression of the cytokine Unpaired 3 (Upd3) in Drosophila and its ortholog, IL-6, in mice. CNS-derived Upd3/IL-6 activated the JAK-STAT pathway in skeletal muscle, which caused muscle mitochondrial dysfunction and impaired motor function. We observed similar phenotypes after expressing toxic amyloid-β (Aβ42) in the CNS. Infection and chronic disease therefore activate a systemic brain-muscle signaling axis in which CNS-derived cytokines bypass the connectome and directly regulate muscle physiology, highlighting IL-6 as a therapeutic target to treat disease-associated muscle dysfunction.
{"title":"Infection and chronic disease activate a systemic brain-muscle signaling axis","authors":"Shuo Yang, Meijie Tian, Yulong Dai, Rong Wang, Shigehiro Yamada, Shengyong Feng, Yunyun Wang, Deepak Chhangani, Tiffany Ou, Wenle Li, Xuan Guo, Jennifer McAdow, Diego E. Rincon-Limas, Xin Yin, Wanbo Tai, Gong Cheng, Aaron Johnson","doi":"10.1126/sciimmunol.adm7908","DOIUrl":"10.1126/sciimmunol.adm7908","url":null,"abstract":"<div >Infections and neurodegenerative diseases induce neuroinflammation, but affected individuals often show nonneural symptoms including muscle pain and muscle fatigue. The molecular pathways by which neuroinflammation causes pathologies outside the central nervous system (CNS) are poorly understood. We developed multiple models to investigate the impact of CNS stressors on motor function and found that <i>Escherichia coli</i> infections and SARS-CoV-2 protein expression caused reactive oxygen species (ROS) to accumulate in the brain. ROS induced expression of the cytokine Unpaired 3 (Upd3) in <i>Drosophila</i> and its ortholog, IL-6, in mice. CNS-derived Upd3/IL-6 activated the JAK-STAT pathway in skeletal muscle, which caused muscle mitochondrial dysfunction and impaired motor function. We observed similar phenotypes after expressing toxic amyloid-β (Aβ42) in the CNS. Infection and chronic disease therefore activate a systemic brain-muscle signaling axis in which CNS-derived cytokines bypass the connectome and directly regulate muscle physiology, highlighting IL-6 as a therapeutic target to treat disease-associated muscle dysfunction.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141601725","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 : 2024-07-12DOI: 10.1126/sciimmunol.adn0178
Kaixin Liang, Katherine C. Barnett, Martin Hsu, Wei-Chun Chou, Sachendra S. Bais, Kristina Riebe, Yuying Xie, Tuong Thien Nguyen, Thomas H. Oguin III, Kevin M. Vannella, Stephen M. Hewitt, Daniel S. Chertow, Maria Blasi, Gregory D. Sempowski, Amelia Karlsson, Beverly H. Koller, Deborah J. Lenschow, Scott H. Randell, Jenny P.-Y. Ting
Virus-induced cell death is a key contributor to COVID-19 pathology. Cell death induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well studied in myeloid cells but less in its primary host cell type, angiotensin-converting enzyme 2 (ACE2)–expressing human airway epithelia (HAE). SARS-CoV-2 induces apoptosis, necroptosis, and pyroptosis in HAE organotypic cultures. Single-cell and limiting-dilution analysis revealed that necroptosis is the primary cell death event in infected cells, whereas uninfected bystanders undergo apoptosis, and pyroptosis occurs later during infection. Mechanistically, necroptosis is induced by viral Z-RNA binding to Z-DNA–binding protein 1 (ZBP1) in HAE and lung tissues from patients with COVID-19. The Delta (B.1.617.2) variant, which causes more severe disease than Omicron (B1.1.529) in humans, is associated with orders of magnitude–greater Z-RNA/ZBP1 interactions, necroptosis, and disease severity in animal models. Thus, Delta induces robust ZBP1-mediated necroptosis and more disease severity.
{"title":"Initiator cell death event induced by SARS-CoV-2 in the human airway epithelium","authors":"Kaixin Liang, Katherine C. Barnett, Martin Hsu, Wei-Chun Chou, Sachendra S. Bais, Kristina Riebe, Yuying Xie, Tuong Thien Nguyen, Thomas H. Oguin III, Kevin M. Vannella, Stephen M. Hewitt, Daniel S. Chertow, Maria Blasi, Gregory D. Sempowski, Amelia Karlsson, Beverly H. Koller, Deborah J. Lenschow, Scott H. Randell, Jenny P.-Y. Ting","doi":"10.1126/sciimmunol.adn0178","DOIUrl":"10.1126/sciimmunol.adn0178","url":null,"abstract":"<div >Virus-induced cell death is a key contributor to COVID-19 pathology. Cell death induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is well studied in myeloid cells but less in its primary host cell type, angiotensin-converting enzyme 2 (ACE2)–expressing human airway epithelia (HAE). SARS-CoV-2 induces apoptosis, necroptosis, and pyroptosis in HAE organotypic cultures. Single-cell and limiting-dilution analysis revealed that necroptosis is the primary cell death event in infected cells, whereas uninfected bystanders undergo apoptosis, and pyroptosis occurs later during infection. Mechanistically, necroptosis is induced by viral Z-RNA binding to Z-DNA–binding protein 1 (ZBP1) in HAE and lung tissues from patients with COVID-19. The Delta (B.1.617.2) variant, which causes more severe disease than Omicron (B1.1.529) in humans, is associated with orders of magnitude–greater Z-RNA/ZBP1 interactions, necroptosis, and disease severity in animal models. Thus, Delta induces robust ZBP1-mediated necroptosis and more disease severity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adn0178","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141601726","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 : 2024-07-12DOI: 10.1126/sciimmunol.adp8170
Lok-Yin Roy Wong, Stanley Perlman
Upon SARS-CoV-2 infection, infected cells undergo necroptosis, whereas delayed apoptosis and pyroptosis occur in uninfected, bystander cells, thus providing a plausible explanation for the extensive injury among myriad uninfected cells.
{"title":"A confusion of pathways: Discerning cell death mechanisms in SARS-CoV-2 infection","authors":"Lok-Yin Roy Wong, Stanley Perlman","doi":"10.1126/sciimmunol.adp8170","DOIUrl":"10.1126/sciimmunol.adp8170","url":null,"abstract":"<div >Upon SARS-CoV-2 infection, infected cells undergo necroptosis, whereas delayed apoptosis and pyroptosis occur in uninfected, bystander cells, thus providing a plausible explanation for the extensive injury among myriad uninfected cells.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141601724","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 : 2024-07-05DOI: 10.1126/sciimmunol.adm8185
Yanick J. Crow, Jean-Laurent Casanova
The past 20 years have seen the definition of human monogenic disorders and their autoimmune phenocopies underlying either defective or enhanced type I interferon (IFN) activity. These disorders delineate the impact of type I IFNs in natural conditions and demonstrate that only a narrow window of type I IFN activity is beneficial. Insufficient type I IFN predisposes humans to life-threatening viral diseases (albeit unexpectedly few) with a central role in immunity to respiratory and cerebral viral infection. Excessive type I IFN, perhaps counterintuitively, appears to underlie a greater number of autoinflammatory and/or autoimmune conditions known as type I interferonopathies, whose study has revealed multiple molecular programs involved in the induction of type I IFN signaling. These observations suggest that the manipulation of type I IFN activity to within a physiological range may be clinically relevant for the prevention and treatment of viral and inflammatory diseases.
在过去的 20 年中，人类单基因遗传疾病及其自身免疫表型被定义为 I 型干扰素（IFN）活性缺陷或增强的基础疾病。这些疾病描述了 I 型干扰素在自然条件下的影响，并证明只有 I 型干扰素活性的狭窄窗口才是有益的。I 型 IFN 不足易使人类患上危及生命的病毒性疾病（尽管数量出乎意料地少），而 I 型 IFN 在呼吸道和脑部病毒感染的免疫中起着核心作用。也许与直觉相反，I 型干扰素过多似乎是更多自身炎症和/或自身免疫疾病的基础，这些疾病被称为 I 型干扰素病，其研究揭示了 I 型干扰素信号诱导过程中涉及的多种分子程序。这些观察结果表明，将 I 型干扰素活性控制在生理范围内可能对预防和治疗病毒性和炎症性疾病有临床意义。
{"title":"Human life within a narrow range: The lethal ups and downs of type I interferons","authors":"Yanick J. Crow, Jean-Laurent Casanova","doi":"10.1126/sciimmunol.adm8185","DOIUrl":"10.1126/sciimmunol.adm8185","url":null,"abstract":"<div >The past 20 years have seen the definition of human monogenic disorders and their autoimmune phenocopies underlying either defective or enhanced type I interferon (IFN) activity. These disorders delineate the impact of type I IFNs in natural conditions and demonstrate that only a narrow window of type I IFN activity is beneficial. Insufficient type I IFN predisposes humans to life-threatening viral diseases (albeit unexpectedly few) with a central role in immunity to respiratory and cerebral viral infection. Excessive type I IFN, perhaps counterintuitively, appears to underlie a greater number of autoinflammatory and/or autoimmune conditions known as type I interferonopathies, whose study has revealed multiple molecular programs involved in the induction of type I IFN signaling. These observations suggest that the manipulation of type I IFN activity to within a physiological range may be clinically relevant for the prevention and treatment of viral and inflammatory diseases.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141538516","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 : 2024-07-05DOI: 10.1126/sciimmunol.adr2965
Giusy Della Gatta, Asha Pillai
Lineage-specific effects of upstream promoters affect ST2 expression and effector function in TH1 cells.
上游启动子的系特异性效应会影响 ST2 在 TH1 细胞中的表达和效应功能。
{"title":"A CHip off the old block","authors":"Giusy Della Gatta, Asha Pillai","doi":"10.1126/sciimmunol.adr2965","DOIUrl":"10.1126/sciimmunol.adr2965","url":null,"abstract":"<div >Lineage-specific effects of upstream promoters affect ST2 expression and effector function in T<sub>H</sub>1 cells.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141538513","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 : 2024-07-05DOI: 10.1126/sciimmunol.adl1965
Emma L. Houlder, Koen A. Stam, Jan Pieter R. Koopman, Marion H. König, Marijke C. C. Langenberg, Marie-Astrid Hoogerwerf, Paula Niewold, Friederike Sonnet, Jacqueline J. Janse, Miriam Casacuberta Partal, Jeroen C. Sijtsma, Laura H. M. de Bes-Roeleveld, Yvonne C. M. Kruize, Maria Yazdanbakhsh, Meta Roestenberg
Schistosomiasis is an infection caused by contact with Schistosoma-contaminated water and affects more than 230 million people worldwide with varying morbidity. The roles of T helper 2 (TH2) cells and regulatory immune responses in chronic infection are well documented, but less is known about human immune responses during acute infection. Here, we comprehensively map immune responses during controlled human Schistosoma mansoni infection using male or female cercariae. Immune responses to male or female parasite single-sex infection were comparable. An early TH1-biased inflammatory response was observed at week 4 after infection, which was particularly apparent in individuals experiencing symptoms of acute schistosomiasis. By week 8 after infection, inflammatory responses were followed by an expansion of TH2 and regulatory cell subsets. This study demonstrates the shift from TH1 to both TH2 and regulatory responses, typical of chronic schistosomiasis, in the absence of egg production and provides immunological insight into the clinical manifestations of acute schistosomiasis.
{"title":"Early symptom-associated inflammatory responses shift to type 2 responses in controlled human schistosome infection","authors":"Emma L. Houlder, Koen A. Stam, Jan Pieter R. Koopman, Marion H. König, Marijke C. C. Langenberg, Marie-Astrid Hoogerwerf, Paula Niewold, Friederike Sonnet, Jacqueline J. Janse, Miriam Casacuberta Partal, Jeroen C. Sijtsma, Laura H. M. de Bes-Roeleveld, Yvonne C. M. Kruize, Maria Yazdanbakhsh, Meta Roestenberg","doi":"10.1126/sciimmunol.adl1965","DOIUrl":"10.1126/sciimmunol.adl1965","url":null,"abstract":"<div >Schistosomiasis is an infection caused by contact with <i>Schistosoma</i>-contaminated water and affects more than 230 million people worldwide with varying morbidity. The roles of T helper 2 (T<sub>H</sub>2) cells and regulatory immune responses in chronic infection are well documented, but less is known about human immune responses during acute infection. Here, we comprehensively map immune responses during controlled human <i>Schistosoma mansoni</i> infection using male or female cercariae. Immune responses to male or female parasite single-sex infection were comparable. An early T<sub>H</sub>1-biased inflammatory response was observed at week 4 after infection, which was particularly apparent in individuals experiencing symptoms of acute schistosomiasis. By week 8 after infection, inflammatory responses were followed by an expansion of T<sub>H</sub>2 and regulatory cell subsets. This study demonstrates the shift from T<sub>H</sub>1 to both T<sub>H</sub>2 and regulatory responses, typical of chronic schistosomiasis, in the absence of egg production and provides immunological insight into the clinical manifestations of acute schistosomiasis.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adl1965","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141538514","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 : 2024-07-05DOI: 10.1126/sciimmunol.adf2047
Diana Castaño, Sidney Wang, Segovia Atencio-Garcia, Emily J. Shields, Maria C. Rico, Hannah Sharpe, Jacinta Bustamante, Allan Feng, Carole Le Coz, Neil Romberg, John W. Tobias, Paul J. Utz, Sarah E. Henrickson, Jean-Laurent Casanova, Roberto Bonasio, Michela Locci
T follicular regulatory (Tfr) cells can counteract the B cell helper activity of T follicular helper (Tfh) cells and hinder the production of antibodies against self-antigens or allergens. A mechanistic understanding of the cytokines initiating the differentiation of human regulatory T (Treg) cells into Tfr cells is still missing. Herein, we report that low doses of the pro-Tfh cytokine interleukin-12 (IL-12) drive the induction of a Tfr cell program on activated human Treg cells while also preserving their regulatory function. Mechanistically, we found that IL-12 led to STAT4 (signal transducer and activator of transcription 4) phosphorylation and binding to IL-12–driven follicular signature genes. Patients with inborn errors of immunity in the IL12RB1 gene presented with a strong decrease in circulating Tfr cells and produced higher levels of anti-actin autoantibodies in vivo. Overall, this study unveils IL-12 as an inducer of Tfr cell differentiation in vivo and provides an approach for the in vitro generation of human Tfr-like cells.
{"title":"IL-12 drives the differentiation of human T follicular regulatory cells","authors":"Diana Castaño, Sidney Wang, Segovia Atencio-Garcia, Emily J. Shields, Maria C. Rico, Hannah Sharpe, Jacinta Bustamante, Allan Feng, Carole Le Coz, Neil Romberg, John W. Tobias, Paul J. Utz, Sarah E. Henrickson, Jean-Laurent Casanova, Roberto Bonasio, Michela Locci","doi":"10.1126/sciimmunol.adf2047","DOIUrl":"10.1126/sciimmunol.adf2047","url":null,"abstract":"<div >T follicular regulatory (T<sub>fr</sub>) cells can counteract the B cell helper activity of T follicular helper (T<sub>fh</sub>) cells and hinder the production of antibodies against self-antigens or allergens. A mechanistic understanding of the cytokines initiating the differentiation of human regulatory T (T<sub>reg</sub>) cells into T<sub>fr</sub> cells is still missing. Herein, we report that low doses of the pro-T<sub>fh</sub> cytokine interleukin-12 (IL-12) drive the induction of a T<sub>fr</sub> cell program on activated human T<sub>reg</sub> cells while also preserving their regulatory function. Mechanistically, we found that IL-12 led to STAT4 (signal transducer and activator of transcription 4) phosphorylation and binding to IL-12–driven follicular signature genes. Patients with inborn errors of immunity in the <i>IL12RB1</i> gene presented with a strong decrease in circulating T<sub>fr</sub> cells and produced higher levels of anti-actin autoantibodies in vivo. Overall, this study unveils IL-12 as an inducer of T<sub>fr</sub> cell differentiation in vivo and provides an approach for the in vitro generation of human T<sub>fr</sub>-like cells.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141538517","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 : 2024-07-05DOI: 10.1126/sciimmunol.adr2967
Andre Monteleone, Gabriel K. Griffin
Histone demethylation by PHF8 initiates innate immune signaling in acute myeloid leukemia, elucidating a novel therapeutic strategy.
PHF8 的组蛋白去甲基化启动了急性髓性白血病的先天免疫信号转导，阐明了一种新的治疗策略。
{"title":"Histone demethylation tones down leukemia through innate immunity","authors":"Andre Monteleone, Gabriel K. Griffin","doi":"10.1126/sciimmunol.adr2967","DOIUrl":"10.1126/sciimmunol.adr2967","url":null,"abstract":"<div >Histone demethylation by PHF8 initiates innate immune signaling in acute myeloid leukemia, elucidating a novel therapeutic strategy.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141538515","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 : 2024-06-28DOI: 10.1126/sciimmunol.adj8356
Erin D. Lucas, Matthew A. Huggins, Changwei Peng, Christine O’Connor, Abigail R. Gress, Claire E. Thefaine, Emma M. Dehm, Yoshiaki Kubota, Stephen C. Jameson, Sara E. Hamilton
KLRG1+ CD8 T cells persist for months after clearance of acute infections and maintain high levels of effector molecules, contributing protective immunity against systemic pathogens. Upon secondary infection, these long-lived effector cells (LLECs) are incapable of forming other circulating KLRG1− memory subsets such as central and effector memory T cells. Thus, KLRG1+ memory T cells are frequently referred to as a terminally differentiated population that is relatively short lived. Here, we show that after viral infection of mice, effector cells derived from LLECs rapidly enter nonlymphoid tissues and reduce pathogen burden but are largely dependent on receiving antigen cues from vascular endothelial cells. Single-cell RNA sequencing reveals that secondary memory cells in nonlymphoid tissues arising from either KLRG1+ or KLRG1− memory precursors develop a similar resident memory transcriptional signature. Thus, although LLECs cannot differentiate into other circulating memory populations, they still retain the flexibility to enter tissues and establish residency.
KLRG1 + CD8 T 细胞在急性感染清除后可存活数月，并保持高水平的效应分子，对全身性病原体产生保护性免疫力。二次感染后，这些长效效应细胞（LLECs）无法形成其他循环的 KLRG1 - 记忆亚群，如中枢记忆 T 细胞和效应记忆 T 细胞。因此，KLRG1 + 记忆 T 细胞经常被称为寿命相对较短的终末分化群体。在这里，我们发现在小鼠受到病毒感染后，来自 LLECs 的效应细胞会迅速进入非淋巴组织并减轻病原体的负担，但在很大程度上依赖于从血管内皮细胞接收抗原线索。单细胞 RNA 测序显示，非淋巴组织中由 KLRG1 + 或 KLRG1 - 记忆前体产生的次级记忆细胞具有类似的常驻记忆转录特征。因此，虽然 LLECs 无法分化成其他循环记忆群体，但它们仍能灵活地进入组织并建立驻留。
{"title":"Circulating KLRG1+ long-lived effector memory T cells retain the flexibility to become tissue resident","authors":"Erin D. Lucas, Matthew A. Huggins, Changwei Peng, Christine O’Connor, Abigail R. Gress, Claire E. Thefaine, Emma M. Dehm, Yoshiaki Kubota, Stephen C. Jameson, Sara E. Hamilton","doi":"10.1126/sciimmunol.adj8356","DOIUrl":"10.1126/sciimmunol.adj8356","url":null,"abstract":"<div >KLRG1<sup>+</sup> CD8 T cells persist for months after clearance of acute infections and maintain high levels of effector molecules, contributing protective immunity against systemic pathogens. Upon secondary infection, these long-lived effector cells (LLECs) are incapable of forming other circulating KLRG1<sup>−</sup> memory subsets such as central and effector memory T cells. Thus, KLRG1<sup>+</sup> memory T cells are frequently referred to as a terminally differentiated population that is relatively short lived. Here, we show that after viral infection of mice, effector cells derived from LLECs rapidly enter nonlymphoid tissues and reduce pathogen burden but are largely dependent on receiving antigen cues from vascular endothelial cells. Single-cell RNA sequencing reveals that secondary memory cells in nonlymphoid tissues arising from either KLRG1<sup>+</sup> or KLRG1<sup>−</sup> memory precursors develop a similar resident memory transcriptional signature. Thus, although LLECs cannot differentiate into other circulating memory populations, they still retain the flexibility to enter tissues and establish residency.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141463027","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 : 2024-06-28DOI: 10.1126/sciimmunol.adj2898
Miguel de Jesus, Alexander H. Settle, Daan Vorselen, Thomas K. Gaetjens, Michael Galiano, Yevgeniy Romin, Esther Lee, Yung Yu Wong, Tian-Ming Fu, Endi Santosa, Benjamin Y. Winer, Fella Tamzalit, Mitchell S. Wang, Anthony Santella, Zhirong Bao, Joseph C. Sun, Pavak Shah, Julie A. Theriot, Steven M. Abel, Morgan Huse
Immune cells have intensely physical lifestyles characterized by structural plasticity and force exertion. To investigate whether specific immune functions require stereotyped mechanical outputs, we used super-resolution traction force microscopy to compare the immune synapses formed by cytotoxic T cells with contacts formed by other T cell subsets and by macrophages. T cell synapses were globally compressive, which was fundamentally different from the pulling and pinching associated with macrophage phagocytosis. Spectral decomposition of force exertion patterns from each cell type linked cytotoxicity to compressive strength, local protrusiveness, and the induction of complex, asymmetric topography. These features were validated as cytotoxic drivers by genetic disruption of cytoskeletal regulators, live imaging of synaptic secretion, and in silico analysis of interfacial distortion. Synapse architecture and force exertion were sensitive to target stiffness and size, suggesting that the mechanical potentiation of killing is biophysically adaptive. We conclude that cellular cytotoxicity and, by implication, other effector responses are supported by specialized patterns of efferent force.
{"title":"Single-cell topographical profiling of the immune synapse reveals a biomechanical signature of cytotoxicity","authors":"Miguel de Jesus, Alexander H. Settle, Daan Vorselen, Thomas K. Gaetjens, Michael Galiano, Yevgeniy Romin, Esther Lee, Yung Yu Wong, Tian-Ming Fu, Endi Santosa, Benjamin Y. Winer, Fella Tamzalit, Mitchell S. Wang, Anthony Santella, Zhirong Bao, Joseph C. Sun, Pavak Shah, Julie A. Theriot, Steven M. Abel, Morgan Huse","doi":"10.1126/sciimmunol.adj2898","DOIUrl":"10.1126/sciimmunol.adj2898","url":null,"abstract":"<div >Immune cells have intensely physical lifestyles characterized by structural plasticity and force exertion. To investigate whether specific immune functions require stereotyped mechanical outputs, we used super-resolution traction force microscopy to compare the immune synapses formed by cytotoxic T cells with contacts formed by other T cell subsets and by macrophages. T cell synapses were globally compressive, which was fundamentally different from the pulling and pinching associated with macrophage phagocytosis. Spectral decomposition of force exertion patterns from each cell type linked cytotoxicity to compressive strength, local protrusiveness, and the induction of complex, asymmetric topography. These features were validated as cytotoxic drivers by genetic disruption of cytoskeletal regulators, live imaging of synaptic secretion, and in silico analysis of interfacial distortion. Synapse architecture and force exertion were sensitive to target stiffness and size, suggesting that the mechanical potentiation of killing is biophysically adaptive. We conclude that cellular cytotoxicity and, by implication, other effector responses are supported by specialized patterns of efferent force.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":null,"pages":null},"PeriodicalIF":17.6,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141463010","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}
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