Pub Date : 2024-12-13DOI: 10.1126/sciimmunol.ads5122
Jan Petersen, Carmen Llerena, Bagher Golzarroshan, Camilla Faoro, Frederic Triebel, Jamie Rossjohn
T cell activity is governed by T cell receptor (TCR) signaling and constrained by immune checkpoint molecules, including programmed cell death protein 1 (PD-1), cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), and lymphocyte activation gene 3 (LAG-3). The basis for how LAG-3 binds to human leukocyte antigen class II molecules (HLA-II) remains unknown. Here, we present the 3.4-angstrom crystal structure of a LAG-3–peptide–HLA-II complex and probe the energetics of the complex interface. Coincident with the HLA-II binding site of the ancestrally related, monomeric CD4 receptor, the LAG-3 homodimer laterally engages two HLA-II molecules via distal D1 domain surfaces, imposing a 38° angular offset. The LAG-3–HLA-II interface is discontinuous and lacks involvement of the D1 extra loop, a binding site for anti–LAG-3 therapeutic monoclonal antibodies. Upon HLA-II binding, intrinsically mobile loops of the LAG-3 molecule become ordered, with contact residues highly conserved across HLA-DR, DQ, and DP allomorphs. Our data provide a structural foundation for development of immunomodulatory approaches targeting LAG-3.
{"title":"Crystal structure of the human LAG-3–HLA-DR1–peptide complex","authors":"Jan Petersen, Carmen Llerena, Bagher Golzarroshan, Camilla Faoro, Frederic Triebel, Jamie Rossjohn","doi":"10.1126/sciimmunol.ads5122","DOIUrl":"https://doi.org/10.1126/sciimmunol.ads5122","url":null,"abstract":"T cell activity is governed by T cell receptor (TCR) signaling and constrained by immune checkpoint molecules, including programmed cell death protein 1 (PD-1), cytotoxic T lymphocyte–associated antigen 4 (CTLA-4), and lymphocyte activation gene 3 (LAG-3). The basis for how LAG-3 binds to human leukocyte antigen class II molecules (HLA-II) remains unknown. Here, we present the 3.4-angstrom crystal structure of a LAG-3–peptide–HLA-II complex and probe the energetics of the complex interface. Coincident with the HLA-II binding site of the ancestrally related, monomeric CD4 receptor, the LAG-3 homodimer laterally engages two HLA-II molecules via distal D1 domain surfaces, imposing a 38° angular offset. The LAG-3–HLA-II interface is discontinuous and lacks involvement of the D1 extra loop, a binding site for anti–LAG-3 therapeutic monoclonal antibodies. Upon HLA-II binding, intrinsically mobile loops of the LAG-3 molecule become ordered, with contact residues highly conserved across HLA-DR, DQ, and DP allomorphs. Our data provide a structural foundation for development of immunomodulatory approaches targeting LAG-3.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"5 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142815991","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 : 2024-12-13DOI: 10.1126/sciimmunol.adl4613
Yavuz F. Yazicioglu, Eros Marin, Hana F. Andrew, Karolina Bentkowska, Julia C. Johnstone, Robert Mitchell, Zhi Yi Wong, Kristina Zec, Joannah Fergusson, Mariana Borsa, Iwan G. A. Raza, Moustafa Attar, Mohammad Ali, Barbara Kronsteiner, Izadora L. Furlani, James I. MacRae, Michael J. Devine, Mark Coles, Christopher D. Buckley, Susanna J. Dunachie, Alexander J. Clarke
The rapid proliferation of germinal center (GC) B cells requires metabolic reprogramming to meet energy demands, yet these metabolic processes are poorly understood. By integrating metabolomic and transcriptomic profiling of GC B cells, we identified that asparagine (Asn) metabolism was highly up-regulated and essential for B cell function. Asparagine synthetase (ASNS) was up-regulated after B cell activation through the integrated stress response sensor GCN2. Conditional deletion of Asns in B cells impaired survival and proliferation in low Asn conditions. Removal of environmental Asn by asparaginase or dietary restriction compromised the GC reaction, impairing affinity maturation and the humoral response to influenza infection. Furthermore, metabolic adaptation to the absence of Asn required ASNS, and oxidative phosphorylation, mitochondrial homeostasis, and synthesis of nucleotides were particularly sensitive to Asn deprivation. These findings demonstrate that Asn metabolism acts as a key regulator of B cell function and GC homeostasis.
生殖中心（GC）B细胞的快速增殖需要进行代谢重编程以满足能量需求，但人们对这些代谢过程知之甚少。通过整合 GC B 细胞的代谢组学和转录组学图谱，我们发现天冬酰胺（Asn）代谢高度上调，并且对 B 细胞功能至关重要。天冬酰胺合成酶（ASNS）在 B 细胞激活后通过综合应激反应传感器 GCN2 上调。在低天冬酰胺条件下，B细胞中条件性缺失的天冬酰胺合成酶（ASNS）会影响其存活和增殖。通过天冬酰胺酶或饮食限制去除环境中的Asn会影响GC反应，损害亲和力成熟和对流感感染的体液反应。此外，新陈代谢对缺乏 Asn 的适应需要 ASNS，氧化磷酸化、线粒体平衡和核苷酸合成对 Asn 剥夺特别敏感。这些发现表明，Asn 代谢是 B 细胞功能和 GC 平衡的关键调节因子。
{"title":"Asparagine availability controls germinal center B cell homeostasis","authors":"Yavuz F. Yazicioglu, Eros Marin, Hana F. Andrew, Karolina Bentkowska, Julia C. Johnstone, Robert Mitchell, Zhi Yi Wong, Kristina Zec, Joannah Fergusson, Mariana Borsa, Iwan G. A. Raza, Moustafa Attar, Mohammad Ali, Barbara Kronsteiner, Izadora L. Furlani, James I. MacRae, Michael J. Devine, Mark Coles, Christopher D. Buckley, Susanna J. Dunachie, Alexander J. Clarke","doi":"10.1126/sciimmunol.adl4613","DOIUrl":"https://doi.org/10.1126/sciimmunol.adl4613","url":null,"abstract":"The rapid proliferation of germinal center (GC) B cells requires metabolic reprogramming to meet energy demands, yet these metabolic processes are poorly understood. By integrating metabolomic and transcriptomic profiling of GC B cells, we identified that asparagine (Asn) metabolism was highly up-regulated and essential for B cell function. Asparagine synthetase (ASNS) was up-regulated after B cell activation through the integrated stress response sensor GCN2. Conditional deletion of <jats:italic>Asns</jats:italic> in B cells impaired survival and proliferation in low Asn conditions. Removal of environmental Asn by asparaginase or dietary restriction compromised the GC reaction, impairing affinity maturation and the humoral response to influenza infection. Furthermore, metabolic adaptation to the absence of Asn required ASNS, and oxidative phosphorylation, mitochondrial homeostasis, and synthesis of nucleotides were particularly sensitive to Asn deprivation. These findings demonstrate that Asn metabolism acts as a key regulator of B cell function and GC homeostasis.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"233 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142815923","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 : 2024-12-13DOI: 10.1126/sciimmunol.ado5951
Thomas J. Scriba, Mahlatse Maseeme, Carly Young, Laura Taylor, Alasdair J. Leslie
Mycobacterium tuberculosis ( M.tb ) is a bacterial pathogen that has evolved in humans, and its interactions with the host are complex and best studied in humans. Myriad immune pathways are involved in infection control, granuloma formation, and progression to tuberculosis (TB) disease. Inflammatory cells, such as macrophages, neutrophils, conventional and unconventional T cells, B cells, NK cells, and innate lymphoid cells, interact via cytokines, cell-cell communication, and eicosanoid signaling to contain or eliminate infection but can alternatively mediate pathological changes required for pathogen transmission. Clinical manifestations include pulmonary and extrapulmonary TB, as well as post-TB lung disease. Risk factors for TB progression, in turn, largely relate to immune status and, apart from traditional chemotherapy, interventions primarily target immune mechanisms, highlighting the critical role of immunopathology in TB. Maintaining a balance between effector mechanisms to achieve protective immunity and avoid detrimental inflammation is central to the immunopathogenesis of TB. Many research gaps remain and deserve prioritization to improve our understanding of human TB immunopathogenesis.
{"title":"Immunopathology in human tuberculosis","authors":"Thomas J. Scriba, Mahlatse Maseeme, Carly Young, Laura Taylor, Alasdair J. Leslie","doi":"10.1126/sciimmunol.ado5951","DOIUrl":"https://doi.org/10.1126/sciimmunol.ado5951","url":null,"abstract":"<jats:italic>Mycobacterium tuberculosis</jats:italic> ( <jats:italic>M.tb</jats:italic> ) is a bacterial pathogen that has evolved in humans, and its interactions with the host are complex and best studied in humans. Myriad immune pathways are involved in infection control, granuloma formation, and progression to tuberculosis (TB) disease. Inflammatory cells, such as macrophages, neutrophils, conventional and unconventional T cells, B cells, NK cells, and innate lymphoid cells, interact via cytokines, cell-cell communication, and eicosanoid signaling to contain or eliminate infection but can alternatively mediate pathological changes required for pathogen transmission. Clinical manifestations include pulmonary and extrapulmonary TB, as well as post-TB lung disease. Risk factors for TB progression, in turn, largely relate to immune status and, apart from traditional chemotherapy, interventions primarily target immune mechanisms, highlighting the critical role of immunopathology in TB. Maintaining a balance between effector mechanisms to achieve protective immunity and avoid detrimental inflammation is central to the immunopathogenesis of TB. Many research gaps remain and deserve prioritization to improve our understanding of human TB immunopathogenesis.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"29 1","pages":""},"PeriodicalIF":24.8,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142815922","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 : 2024-12-13DOI: 10.1126/sciimmunol.adu6398
{"title":"Erratum for the Research Article \"Acquisition of suppressive function by conventional T cells limits antitumor immunity upon T<sub>reg</sub> depletion\" by S. K. Whiteside <i>et al</i>.","authors":"","doi":"10.1126/sciimmunol.adu6398","DOIUrl":"https://doi.org/10.1126/sciimmunol.adu6398","url":null,"abstract":"","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"9 102","pages":"eadu6398"},"PeriodicalIF":17.6,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142822693","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.adu8807
Kelly Butler, Adam Williams
Lymph node IL-2 microniches guide development of T H 2 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 T H 2 formation in allergic asthma","authors":"Kelly Butler, Adam Williams","doi":"10.1126/sciimmunol.adu8807","DOIUrl":"https://doi.org/10.1126/sciimmunol.adu8807","url":null,"abstract":"Lymph node IL-2 microniches guide development of T <jats:sub>H</jats:sub> 2 cells through induction of Blimp-1 expression and an IL-10–positive feedback loop.","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"20 1","pages":""},"PeriodicalIF":24.8,"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 E 2 (PGE 2 ) as a major immune regulatory mechanism of heGDH. The induction of PGE 2 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":"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}
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":"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}
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":"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}
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":"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}
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}
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