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
{"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":"https://doi.org/10.1126/sciimmunol.adl1467","url":null,"abstract":"The molecular mechanisms by which worm parasites evade host immunity are incompletely understood. In a mouse model of intestinal helminth infection using <jats:italic>Heligmosomoides polygyrus bakeri</jats:italic> ( <jats:italic>Hpb</jats:italic> ), 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 <jats:sub>2</jats:sub> (PGE <jats:sub>2</jats:sub> ) as a major immune regulatory mechanism of heGDH. The induction of PGE <jats:sub>2</jats: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.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"84 1","pages":""},"PeriodicalIF":24.8,"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}
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
{"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":"https://doi.org/10.1126/sciimmunol.adp7951","url":null,"abstract":"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 <jats:italic>Staphylococcus aureus</jats:italic> or influenza, ongoing pulmonary <jats:italic>Mycobacterium tuberculosis</jats:italic> 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.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"124 1","pages":""},"PeriodicalIF":24.8,"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}
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
{"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":"https://doi.org/10.1126/sciimmunol.adp9841","url":null,"abstract":"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 <jats:sup>+</jats:sup> MAIT1 cells remained stable in all experimental settings, after adoptive transfer or acute <jats:italic>Legionella</jats:italic> or <jats:italic>Francisella</jats:italic> infection, RORγt <jats:sup>+</jats:sup> MAIT17 cells could undergo phenotypic and functional conversion into both RORγt <jats:sup>+</jats:sup> T-bet <jats:sup>+</jats:sup> MAIT1/17 and RORγt <jats:sup>−</jats:sup> T-bet <jats:sup>+</jats: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.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"5 1","pages":""},"PeriodicalIF":24.8,"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}
{"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":"https://doi.org/10.1126/sciimmunol.adu8805","url":null,"abstract":"<p><p>Endoglycosidase CU43 removes IgG Fc glycans, inhibits IgG effector functions, and prevents pathology in multiple disease models.</p>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 102","pages":"eadu8805"},"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}
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
{"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}
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
{"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}
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
{"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}
{"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}
Olivier Demaria, Guillaume Habif, Marie Vetizou, Laurent Gauthier, Romain Remark, Laura Chiossone, Constance Vagne, Lucas Rebuffet, Rachel Courtois, Caroline Denis, François Le Floch, Marianna Muller, Mathilde Girard-Madoux, Séverine Augier, Julie Lopez, Barbara Carrette, Aurélie Maguer, Jean-Baptiste Vallier, Gwendoline Grondin, William Baron, Justine Galluso, Nadia Yessaad, Marilyn Giordano, Léa Simon, Fabien Chanuc, Audrey Blanchard Alvarez, Ivan Perrot, Cécile Bonnafous, Agnès Represa, Benjamin Rossi, Ariane Morel, Yannis Morel, Carine Paturel, Eric Vivier
{"title":"A tetraspecific engager armed with a non-alpha IL-2 variant harnesses natural killer cells against B cell non-Hodgkin lymphoma","authors":"Olivier Demaria, Guillaume Habif, Marie Vetizou, Laurent Gauthier, Romain Remark, Laura Chiossone, Constance Vagne, Lucas Rebuffet, Rachel Courtois, Caroline Denis, François Le Floch, Marianna Muller, Mathilde Girard-Madoux, Séverine Augier, Julie Lopez, Barbara Carrette, Aurélie Maguer, Jean-Baptiste Vallier, Gwendoline Grondin, William Baron, Justine Galluso, Nadia Yessaad, Marilyn Giordano, Léa Simon, Fabien Chanuc, Audrey Blanchard Alvarez, Ivan Perrot, Cécile Bonnafous, Agnès Represa, Benjamin Rossi, Ariane Morel, Yannis Morel, Carine Paturel, Eric Vivier","doi":"10.1126/sciimmunol.adp3720","DOIUrl":"10.1126/sciimmunol.adp3720","url":null,"abstract":"<div >NK cells offer a promising alternative to T cell therapies in cancer. We evaluated IPH6501, a clinical-stage, tetraspecific NK cell engager (NKCE) armed with a non-alpha IL-2 variant (IL-2v), which targets CD20 and was developed for treating B cell non-Hodgkin lymphoma (B-NHL). CD20-NKCE-IL2v boosts NK cell proliferation and cytotoxicity, showing activity against a range of B-NHL cell lines, including those with low CD20 density. Whereas it presented reduced toxicities compared with those commonly associated with T cell therapies, CD20-NKCE-IL2v showed greater killing efficacy over a T cell engager targeting CD20 in in vitro preclinical models. CD20-NKCE-IL2v also increased the cell surface expression of NK cell–activating receptors, leading to activity against CD20-negative tumor cells. In vivo studies in nonhuman primates and tumor mouse models further validated its efficacy and revealed that CD20-NKCE-IL2v induces peripheral NK cell homing at the tumor site. CD20-NKCE-IL2v emerges as a potential alternative in the treatment landscape of B-NHL.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 101","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adp3720","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637594","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yexin Yang, Rebecca S. Treger, Juan Hernandez-Bird, Peiwen Lu, Tianyang Mao, Akiko Iwasaki
{"title":"A B cell screen against endogenous retroviruses identifies glycan-reactive IgM that recognizes a broad array of enveloped viruses","authors":"Yexin Yang, Rebecca S. Treger, Juan Hernandez-Bird, Peiwen Lu, Tianyang Mao, Akiko Iwasaki","doi":"10.1126/sciimmunol.add6608","DOIUrl":"10.1126/sciimmunol.add6608","url":null,"abstract":"<div >Endogenous retroviruses (ERVs), comprising a substantial portion of the vertebrate genome, are remnants of ancient genetic invaders. ERVs with near-intact coding potential reactivate in B cell–deficient mice. To study how B cells contribute to host anti-ERV immunity, we used an antigen-baiting strategy to enrich B cells reactive to ERV surface antigens. We identified ERV-reactive B-1 cells expressing germline-encoded natural IgM antibodies in naïve mice, the level of which further increases upon innate immune sensor stimulation. B cell receptor repertoire profiling of ERV-reactive B-1 cells revealed increased usage of the <i>Igh</i> V<sub>H</sub> gene that gives rise to glycan-specific antibodies targeting terminal <i>N</i>-acetylglucosamine moieties on ERV glycoproteins, which further engage the complement pathway to mediate anti-ERV responses. These same antibodies also recognize glycoproteins of other enveloped viruses but not self-proteins. These results reveal an innate antiviral mechanism of germline-encoded antibodies with broad reactivity to enveloped viruses, which constitutes a natural antibody repertoire capable of preventing the emergence of infectious ERVs.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 101","pages":""},"PeriodicalIF":17.6,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.add6608","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142596857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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