Pub Date : 2024-12-06DOI: 10.1126/sciimmunol.adu8807
Kelly Butler, Adam Williams
Lymph node IL-2 microniches guide development of TH2 cells through induction of Blimp-1 expression and an IL-10–positive feedback loop.
淋巴结IL-2微细胞通过诱导Blimp-1表达和il -10正反馈回路引导t2细胞的发育。
{"title":"It’s the little things in life: Lymph node microniches drive TH2 formation in allergic asthma","authors":"Kelly Butler, Adam Williams","doi":"10.1126/sciimmunol.adu8807","DOIUrl":"10.1126/sciimmunol.adu8807","url":null,"abstract":"<div >Lymph node IL-2 microniches guide development of T<sub>H</sub>2 cells through induction of Blimp-1 expression and an IL-10–positive feedback loop.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 102","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788499","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 : 2024-12-06DOI: 10.1126/sciimmunol.adl1467
Sina Bohnacker, Fiona D. R. Henkel, Franziska Hartung, Arie Geerlof, Sandra Riemer, Ulrich F. Prodjinotho, Eya Ben Salah, André Santos Dias Mourão, Stefan Bohn, Tarvi Teder, Dominique Thomas, Robert Gurke, Christiane Boeckel, Minhaz Ud-Dean, Ann-Christine König, Alessandro Quaranta, Francesca Alessandrini, Antonie Lechner, Benedikt Spitzlberger, Agnieszka M. Kabat, Edward Pearce, Jesper Z. Haeggström, Stefanie M. Hauck, Craig E. Wheelock, Per-Johan Jakobsson, Michael Sattler, David Voehringer, Matthias J. Feige, Clarissa Prazeres da Costa, Julia Esser-von Bieren
The molecular mechanisms by which worm parasites evade host immunity are incompletely understood. In a mouse model of intestinal helminth infection using Heligmosomoides polygyrus bakeri (Hpb), we show that helminthic glutamate dehydrogenase (heGDH) drives parasite chronicity by suppressing macrophage-mediated host defense. Combining RNA-seq, ChIP-seq, and targeted lipidomics, we identify prostaglandin E2 (PGE2) as a major immune regulatory mechanism of heGDH. The induction of PGE2 and other immunoregulatory factors, including IL-12 family cytokines and indoleamine 2,3-dioxygenase 1, by heGDH required p300-mediated histone acetylation, whereas the enzyme’s catalytic activity suppressed the synthesis of type 2–promoting leukotrienes by macrophages via 2-hydroxyglutarate. By contrast, the induction of immunoregulatory factors involved the heGDH N terminus by potentially mediating interactions with cellular targets (CD64 and GPNMB) identified by proteomics. Type 2 cytokines counteracted suppressive effects of heGDH on host defense, indicating that type 2 immunity can limit helminth-driven immune evasion. Thus, helminths harness a ubiquitous metabolic enzyme to epigenetically target type 2 macrophage activation and establish chronicity.
{"title":"A helminth enzyme subverts macrophage-mediated immunity by epigenetic targeting of prostaglandin synthesis","authors":"Sina Bohnacker, Fiona D. R. Henkel, Franziska Hartung, Arie Geerlof, Sandra Riemer, Ulrich F. Prodjinotho, Eya Ben Salah, André Santos Dias Mourão, Stefan Bohn, Tarvi Teder, Dominique Thomas, Robert Gurke, Christiane Boeckel, Minhaz Ud-Dean, Ann-Christine König, Alessandro Quaranta, Francesca Alessandrini, Antonie Lechner, Benedikt Spitzlberger, Agnieszka M. Kabat, Edward Pearce, Jesper Z. Haeggström, Stefanie M. Hauck, Craig E. Wheelock, Per-Johan Jakobsson, Michael Sattler, David Voehringer, Matthias J. Feige, Clarissa Prazeres da Costa, Julia Esser-von Bieren","doi":"10.1126/sciimmunol.adl1467","DOIUrl":"10.1126/sciimmunol.adl1467","url":null,"abstract":"<div >The molecular mechanisms by which worm parasites evade host immunity are incompletely understood. In a mouse model of intestinal helminth infection using <i>Heligmosomoides polygyrus bakeri</i> (<i>Hpb</i>), we show that helminthic glutamate dehydrogenase (heGDH) drives parasite chronicity by suppressing macrophage-mediated host defense. Combining RNA-seq, ChIP-seq, and targeted lipidomics, we identify prostaglandin E<sub>2</sub> (PGE<sub>2</sub>) as a major immune regulatory mechanism of heGDH. The induction of PGE<sub>2</sub> and other immunoregulatory factors, including IL-12 family cytokines and indoleamine 2,3-dioxygenase 1, by heGDH required p300-mediated histone acetylation, whereas the enzyme’s catalytic activity suppressed the synthesis of type 2–promoting leukotrienes by macrophages via 2-hydroxyglutarate. By contrast, the induction of immunoregulatory factors involved the heGDH N terminus by potentially mediating interactions with cellular targets (CD64 and GPNMB) identified by proteomics. Type 2 cytokines counteracted suppressive effects of heGDH on host defense, indicating that type 2 immunity can limit helminth-driven immune evasion. Thus, helminths harness a ubiquitous metabolic enzyme to epigenetically target type 2 macrophage activation and establish chronicity.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 102","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788466","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 : 2024-12-06DOI: 10.1126/sciimmunol.adp7951
Paul J. Baker, Andrea C. Bohrer, Ehydel Castro, Eduardo P. Amaral, Maryonne Snow-Smith, Flor Torres-Juárez, Sydnee T. Gould, Artur T. L. Queiroz, Eduardo R. Fukutani, Cassandra M. Jordan, Jaspal S. Khillan, Kyoungin Cho, Daniel L. Barber, Bruno B. Andrade, Reed F. Johnson, Kerry L. Hilligan, Katrin D. Mayer-Barber
Severity of COVID-19 is affected by multiple factors; however, it is not understood how the inflammatory milieu of the lung at the time of SARS-CoV-2 exposure affects the control of viral replication. Here, we demonstrate that immune events in the mouse lung closely preceding SARS-CoV-2 infection affect viral control and identify innate immune pathways that limit viral replication. Pulmonary inflammatory stimuli including resolved, antecedent respiratory infections with Staphylococcus aureus or influenza, ongoing pulmonary Mycobacterium tuberculosis infection, ovalbumin/alum-induced asthma, or airway administration of TLR ligands and recombinant cytokines all establish an antiviral state in the lung that restricts SARS-CoV-2 replication. In addition to antiviral type I interferons, TNFα and IL-1 potently precondition the lung for enhanced viral control. Our work shows that SARS-CoV-2 may benefit from an immunologically quiescent lung microenvironment and suggests that heterogeneity in pulmonary inflammation preceding SARS-CoV-2 exposure may contribute to variability in disease outcomes.
{"title":"The inflammatory microenvironment of the lung at the time of infection governs innate control of SARS-CoV-2 replication","authors":"Paul J. Baker, Andrea C. Bohrer, Ehydel Castro, Eduardo P. Amaral, Maryonne Snow-Smith, Flor Torres-Juárez, Sydnee T. Gould, Artur T. L. Queiroz, Eduardo R. Fukutani, Cassandra M. Jordan, Jaspal S. Khillan, Kyoungin Cho, Daniel L. Barber, Bruno B. Andrade, Reed F. Johnson, Kerry L. Hilligan, Katrin D. Mayer-Barber","doi":"10.1126/sciimmunol.adp7951","DOIUrl":"10.1126/sciimmunol.adp7951","url":null,"abstract":"<div >Severity of COVID-19 is affected by multiple factors; however, it is not understood how the inflammatory milieu of the lung at the time of SARS-CoV-2 exposure affects the control of viral replication. Here, we demonstrate that immune events in the mouse lung closely preceding SARS-CoV-2 infection affect viral control and identify innate immune pathways that limit viral replication. Pulmonary inflammatory stimuli including resolved, antecedent respiratory infections with <i>Staphylococcus aureus</i> or influenza, ongoing pulmonary <i>Mycobacterium tuberculosis</i> infection, ovalbumin/alum-induced asthma, or airway administration of TLR ligands and recombinant cytokines all establish an antiviral state in the lung that restricts SARS-CoV-2 replication. In addition to antiviral type I interferons, TNFα and IL-1 potently precondition the lung for enhanced viral control. Our work shows that SARS-CoV-2 may benefit from an immunologically quiescent lung microenvironment and suggests that heterogeneity in pulmonary inflammation preceding SARS-CoV-2 exposure may contribute to variability in disease outcomes.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 102","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788497","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 : 2024-12-06DOI: 10.1126/sciimmunol.adp9841
Huimeng Wang, Michael N. T. Souter, Marcela de Lima Moreira, Shihan Li, Yuchen Zhou, Adam G. Nelson, Jinhan Yu, Lucy J. Meehan, Bronwyn S. Meehan, Sidonia B. G. Eckle, Hyun Jae Lee, Jan Schröder, Ashraful Haque, Jeffrey Y. W. Mak, David P. Fairlie, James McCluskey, Zhongfang Wang, Zhenjun Chen, Alexandra J. Corbett
Mucosal-associated invariant T (MAIT) cells are known for their rapid effector functions and antibacterial immune protection. Here, we define the plasticity of interferon-γ (IFN-γ)–producing MAIT1 and interleukin-17A (IL-17A)–producing MAIT17 cell subsets in vivo. Whereas T-bet+ MAIT1 cells remained stable in all experimental settings, after adoptive transfer or acute Legionella or Francisella infection, RORγt+ MAIT17 cells could undergo phenotypic and functional conversion into both RORγt+T-bet+ MAIT1/17 and RORγt−T-bet+ MAIT1 cells. This plasticity ensured that MAIT17 cells played a dominant role in generating antibacterial MAIT1 responses in mucosal tissues. Single-cell transcriptomics revealed that MAIT17-derived MAIT1 cells were distinct from canonical MAIT1 cells yet could migrate out of mucosal tissues to contribute to the global MAIT1 pool in subsequent systemic infections. Human IL-17A–secreting MAIT cells also showed similar functional plasticity. Our findings have broad implications for understanding the role of MAIT cells in combatting infections and their potential utility in MAIT cell–targeted vaccines.
{"title":"MAIT cell plasticity enables functional adaptation that drives antibacterial immune protection","authors":"Huimeng Wang, Michael N. T. Souter, Marcela de Lima Moreira, Shihan Li, Yuchen Zhou, Adam G. Nelson, Jinhan Yu, Lucy J. Meehan, Bronwyn S. Meehan, Sidonia B. G. Eckle, Hyun Jae Lee, Jan Schröder, Ashraful Haque, Jeffrey Y. W. Mak, David P. Fairlie, James McCluskey, Zhongfang Wang, Zhenjun Chen, Alexandra J. Corbett","doi":"10.1126/sciimmunol.adp9841","DOIUrl":"10.1126/sciimmunol.adp9841","url":null,"abstract":"<div >Mucosal-associated invariant T (MAIT) cells are known for their rapid effector functions and antibacterial immune protection. Here, we define the plasticity of interferon-γ (IFN-γ)–producing MAIT1 and interleukin-17A (IL-17A)–producing MAIT17 cell subsets in vivo. Whereas T-bet<sup>+</sup> MAIT1 cells remained stable in all experimental settings, after adoptive transfer or acute <i>Legionella</i> or <i>Francisella</i> infection, RORγt<sup>+</sup> MAIT17 cells could undergo phenotypic and functional conversion into both RORγt<sup>+</sup>T-bet<sup>+</sup> MAIT1/17 and RORγt<sup>−</sup>T-bet<sup>+</sup> MAIT1 cells. This plasticity ensured that MAIT17 cells played a dominant role in generating antibacterial MAIT1 responses in mucosal tissues. Single-cell transcriptomics revealed that MAIT17-derived MAIT1 cells were distinct from canonical MAIT1 cells yet could migrate out of mucosal tissues to contribute to the global MAIT1 pool in subsequent systemic infections. Human IL-17A–secreting MAIT cells also showed similar functional plasticity. Our findings have broad implications for understanding the role of MAIT cells in combatting infections and their potential utility in MAIT cell–targeted vaccines.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 102","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142788498","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 : 2024-12-06DOI: 10.1126/sciimmunol.adu8805
Dana L. E. Vergoossen, Maartje G. Huijbers
Endoglycosidase CU43 removes IgG Fc glycans, inhibits IgG effector functions, and prevents pathology in multiple disease models.
内糖苷酶CU43去除IgG Fc聚糖，抑制IgG效应功能，并在多种疾病模型中预防病理。
{"title":"Removing “flavor” from pathogenic antibodies hits a therapeutic sweet spot","authors":"Dana L. E. Vergoossen, Maartje G. Huijbers","doi":"10.1126/sciimmunol.adu8805","DOIUrl":"10.1126/sciimmunol.adu8805","url":null,"abstract":"<div >Endoglycosidase CU43 removes IgG Fc glycans, inhibits IgG effector functions, and prevents pathology in multiple disease models.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 102","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-12-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142789575","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 : 2024-11-29DOI: 10.1126/sciimmunol.adk2954
Ziang Zhu, Ying Luo, Guohua Lou, Kiddist Yihunie, Safuwra Wizzard, Andrew W. DeVilbiss, Sarah Muh, Chaoyu Ma, Sejal S. Shinde, Jonathan Hoar, Taidou Hu, Nu Zhang, Shyam Biswal, Ralph J. DeBerardinis, Tuoqi Wu, Chen Yao
During persistent antigen stimulation, exhausted CD8+ T cells are continuously replenished by self-renewing stem-like T cells. However, how CD8+ T cells adapt to chronic stimulation remains unclear. Here, we show that persistent antigen stimulation primes chromatin for regulation by the redox-sensing KEAP1-NRF2 pathway. Loss of KEAP1 in T cells impaired control of chronic viral infection. T cell–intrinsic KEAP1 suppressed NRF2 to promote expansion and persistence of virus-specific CD8+ T cells, drive a stem-like T cell response, down-regulate immune checkpoint molecules, and limit T cell receptor (TCR) hyperactivation and apoptosis. NRF2 epigenetically derepressed BACH2 targets and opposed a stem-like program driven by BACH2. In exhausted T cells induced by tonic GD2 chimeric antigen receptor (CAR) signaling, the effects of KEAP1 deficiency were rescued by inhibiting proximal TCR signaling. Enhancing mitochondrial oxidation improved the expansion and survival of KEAP1-deficient CD8+ GD2 CAR T cells and up-regulated markers associated with stem-like cells. Thus, the KEAP1-NRF2 axis regulates stem-like CD8+ T cells and long-term T cell immunity during chronic antigen exposure.
{"title":"The redox sensor KEAP1 facilitates adaptation of T cells to chronic antigen stimulation by preventing hyperactivation","authors":"Ziang Zhu, Ying Luo, Guohua Lou, Kiddist Yihunie, Safuwra Wizzard, Andrew W. DeVilbiss, Sarah Muh, Chaoyu Ma, Sejal S. Shinde, Jonathan Hoar, Taidou Hu, Nu Zhang, Shyam Biswal, Ralph J. DeBerardinis, Tuoqi Wu, Chen Yao","doi":"10.1126/sciimmunol.adk2954","DOIUrl":"10.1126/sciimmunol.adk2954","url":null,"abstract":"<div >During persistent antigen stimulation, exhausted CD8<sup>+</sup> T cells are continuously replenished by self-renewing stem-like T cells. However, how CD8<sup>+</sup> T cells adapt to chronic stimulation remains unclear. Here, we show that persistent antigen stimulation primes chromatin for regulation by the redox-sensing KEAP1-NRF2 pathway. Loss of KEAP1 in T cells impaired control of chronic viral infection. T cell–intrinsic KEAP1 suppressed NRF2 to promote expansion and persistence of virus-specific CD8<sup>+</sup> T cells, drive a stem-like T cell response, down-regulate immune checkpoint molecules, and limit T cell receptor (TCR) hyperactivation and apoptosis. NRF2 epigenetically derepressed BACH2 targets and opposed a stem-like program driven by BACH2. In exhausted T cells induced by tonic GD2 chimeric antigen receptor (CAR) signaling, the effects of KEAP1 deficiency were rescued by inhibiting proximal TCR signaling. Enhancing mitochondrial oxidation improved the expansion and survival of KEAP1-deficient CD8<sup>+</sup> GD2 CAR T cells and up-regulated markers associated with stem-like cells. Thus, the KEAP1-NRF2 axis regulates stem-like CD8<sup>+</sup> T cells and long-term T cell immunity during chronic antigen exposure.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 101","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adk2954","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142753703","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 : 2024-11-22DOI: 10.1126/sciimmunol.adq8796
Bernhard Ransmayr, Sevgi Köstel Bal, Marini Thian, Michael Svaton, Cheryl van de Wetering, Christoph Hafemeister, Anna Segarra-Roca, Jana Block, Alexandra Frohne, Ana Krolo, Melek Yorgun Altunbas, Sevgi Bilgic-Eltan, Ayça Kıykım, Omer Aydiner, Selin Kesim, Sabahat Inanir, Elif Karakoc-Aydiner, Ahmet Ozen, Ümran Aba, Aylin Çomak, Gökçen Dilşa Tuğcu, Robert Pazdzior, Bettina Huber, Matthias Farlik, Stefan Kubicek, Horst von Bernuth, Ingrid Simonitsch-Klupp, Marta Rizzi, Florian Halbritter, Alexei V. Tumanov, Michael J. Kraakman, Ayşe Metin, Irinka Castanon, Baran Erman, Safa Baris, Kaan Boztug
Secondary lymphoid organs (SLOs) provide the confined microenvironment required for stromal cells to interact with immune cells to initiate adaptive immune responses resulting in B cell differentiation. Here, we studied three patients from two families with functional hyposplenism, absence of tonsils, and complete lymph node aplasia, leading to recurrent bacterial and viral infections. We identified biallelic loss-of-function mutations in LTBR, encoding the lymphotoxin beta receptor (LTβR), primarily expressed on stromal cells. Patients with LTβR deficiency had hypogammaglobulinemia, diminished memory B cells, regulatory and follicular T helper cells, and dysregulated expression of several tumor necrosis factor family members. B cell differentiation in an ex vivo coculture system was intact, implying that the observed B cell defects were not intrinsic in nature and instead resulted from LTβR-dependent stromal cell interaction signaling critical for SLO formation. Collectively, we define a human inborn error of immunity caused primarily by a stromal defect affecting the development and function of SLOs.
继发性淋巴器官（SLO）提供了基质细胞与免疫细胞相互作用所需的封闭微环境，从而启动适应性免疫反应，导致 B 细胞分化。在这里，我们对来自两个家族的三名患者进行了研究，他们都患有功能性脾功能低下、扁桃体缺失和淋巴结完全再生障碍，从而导致反复的细菌和病毒感染。我们发现了 LTBR 的双倍功能缺失突变，LTBR 编码主要在基质细胞上表达的淋巴毒素 beta 受体（LTβR）。LTβR缺乏症患者有低丙种球蛋白血症，记忆性B细胞、调节性和滤泡T辅助细胞减少，以及多种肿瘤坏死因子家族成员表达失调。体内外共培养系统中的 B 细胞分化完好无损，这意味着观察到的 B 细胞缺陷不是内在性质的，而是由对 SLO 形成至关重要的 LTβR 依赖性基质细胞相互作用信号导致的。总之，我们定义了一种人类先天性免疫错误，其主要原因是基质缺陷影响了 SLO 的发育和功能。
{"title":"LTβR deficiency causes lymph node aplasia and impaired B cell differentiation","authors":"Bernhard Ransmayr, Sevgi Köstel Bal, Marini Thian, Michael Svaton, Cheryl van de Wetering, Christoph Hafemeister, Anna Segarra-Roca, Jana Block, Alexandra Frohne, Ana Krolo, Melek Yorgun Altunbas, Sevgi Bilgic-Eltan, Ayça Kıykım, Omer Aydiner, Selin Kesim, Sabahat Inanir, Elif Karakoc-Aydiner, Ahmet Ozen, Ümran Aba, Aylin Çomak, Gökçen Dilşa Tuğcu, Robert Pazdzior, Bettina Huber, Matthias Farlik, Stefan Kubicek, Horst von Bernuth, Ingrid Simonitsch-Klupp, Marta Rizzi, Florian Halbritter, Alexei V. Tumanov, Michael J. Kraakman, Ayşe Metin, Irinka Castanon, Baran Erman, Safa Baris, Kaan Boztug","doi":"10.1126/sciimmunol.adq8796","DOIUrl":"10.1126/sciimmunol.adq8796","url":null,"abstract":"<div >Secondary lymphoid organs (SLOs) provide the confined microenvironment required for stromal cells to interact with immune cells to initiate adaptive immune responses resulting in B cell differentiation. Here, we studied three patients from two families with functional hyposplenism, absence of tonsils, and complete lymph node aplasia, leading to recurrent bacterial and viral infections. We identified biallelic loss-of-function mutations in <i>LTBR,</i> encoding the lymphotoxin beta receptor (LTβR), primarily expressed on stromal cells. Patients with LTβR deficiency had hypogammaglobulinemia, diminished memory B cells, regulatory and follicular T helper cells, and dysregulated expression of several tumor necrosis factor family members. B cell differentiation in an ex vivo coculture system was intact, implying that the observed B cell defects were not intrinsic in nature and instead resulted from LTβR-dependent stromal cell interaction signaling critical for SLO formation. Collectively, we define a human inborn error of immunity caused primarily by a stromal defect affecting the development and function of SLOs.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 101","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142690674","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 : 2024-11-22DOI: 10.1126/sciimmunol.adk0412
Jacki E. Heraud-Farlow, Scott R. Taylor, Alistair M. Chalk, Adriana Escudero, Shi-Bin Hu, Ankita Goradia, Tao Sun, Qin Li, Iva Nikolic, Jin Billy Li, Miguel Fidalgo, Diana Guallar, Kaylene J. Simpson, Carl R. Walkley
Adenosine-to-inosine (A-to-I) editing of double-stranded RNA (dsRNA) by ADAR1 is an essential modifier of the immunogenicity of cellular dsRNA. The role of MDA5 in sensing unedited cellular dsRNA and the downstream activation of type I interferon (IFN) signaling are well established. However, we have an incomplete understanding of pathways that modify the response to unedited dsRNA. We performed a genome-wide CRISPR screen and showed that GGNBP2, CNOT10, and CNOT11 interact and regulate sensing of unedited cellular dsRNA. We found that GGNBP2 acts between dsRNA transcription and its cytoplasmic sensing by MDA5. GGNBP2 loss prevented induction of type I IFN and autoinflammation after the loss of ADAR1 editing activity by modifying the subcellular distribution of endogenous A-to-I editing substrates and reducing cytoplasmic dsRNA load. These findings reveal previously undescribed pathways to modify diseases associated with ADAR mutations and may be determinants of response or resistance to small-molecule ADAR1 inhibitors.
ADAR1 对双链 RNA（dsRNA）进行腺苷转肌苷（A-to-I）编辑是细胞 dsRNA 免疫原性的重要调节因子。MDA5 在感知未经编辑的细胞 dsRNA 和下游激活 I 型干扰素（IFN）信号传导中的作用已得到公认。然而，我们对改变对未经编辑的dsRNA的反应的途径的了解并不全面。我们进行了一次全基因组的 CRISPR 筛选，结果显示 GGNBP2、CNOT10 和 CNOT11 相互作用并调控对未经编辑的细胞 dsRNA 的感应。我们发现 GGNBP2 介于 dsRNA 转录和 MDA5 的细胞质感应之间。GGNBP2 的缺失通过改变内源性 A 到 I 编辑底物的亚细胞分布和减少细胞质 dsRNA 负荷，防止了 ADAR1 编辑活性缺失后 I 型 IFN 的诱导和自身炎症。这些发现揭示了以前未曾描述过的改变与 ADAR 突变有关的疾病的途径，并可能是决定对小分子 ADAR1 抑制剂的反应或抗性的因素。
{"title":"GGNBP2 regulates MDA5 sensing triggered by self double-stranded RNA following loss of ADAR1 editing","authors":"Jacki E. Heraud-Farlow, Scott R. Taylor, Alistair M. Chalk, Adriana Escudero, Shi-Bin Hu, Ankita Goradia, Tao Sun, Qin Li, Iva Nikolic, Jin Billy Li, Miguel Fidalgo, Diana Guallar, Kaylene J. Simpson, Carl R. Walkley","doi":"10.1126/sciimmunol.adk0412","DOIUrl":"10.1126/sciimmunol.adk0412","url":null,"abstract":"<div >Adenosine-to-inosine (A-to-I) editing of double-stranded RNA (dsRNA) by ADAR1 is an essential modifier of the immunogenicity of cellular dsRNA. The role of MDA5 in sensing unedited cellular dsRNA and the downstream activation of type I interferon (IFN) signaling are well established. However, we have an incomplete understanding of pathways that modify the response to unedited dsRNA. We performed a genome-wide CRISPR screen and showed that GGNBP2, CNOT10, and CNOT11 interact and regulate sensing of unedited cellular dsRNA. We found that GGNBP2 acts between dsRNA transcription and its cytoplasmic sensing by MDA5. GGNBP2 loss prevented induction of type I IFN and autoinflammation after the loss of ADAR1 editing activity by modifying the subcellular distribution of endogenous A-to-I editing substrates and reducing cytoplasmic dsRNA load. These findings reveal previously undescribed pathways to modify diseases associated with <i>ADAR</i> mutations and may be determinants of response or resistance to small-molecule ADAR1 inhibitors.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 101","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142690675","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}
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}
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