Pub Date : 2026-01-02DOI: 10.1126/sciimmunol.ady2268
Kelly Bruton, Allyssa Phelps, Atai Ariaz, Allison Fang, Tina D. Walker, Jianping Wen, Sharon S. Khavkine-Binstock, Danielle Della Libera, Olivia Mann-Delany, Niels Peter H. Knudsen, Siyon Gadkar, Emily Grydziuszko, Joshua F. E. Koenig, Aidan Gagnon, Susan Waserman, Peter S. Andersen, Manel Jordana
Long-lived immunoglobulin E (IgE) responses against innocuous environmental and dietary antigens (Ags) are maintained by an IgG1-dominant memory B cell (MBC) compartment primed for interleukin-4 (IL-4) responsiveness. The plasticity of the MBC compartment destined for IgE class switch recombination remains poorly understood. In this work, we report critical IL-4 and IL-13 dependency for the pathogenic IgE fate of type 2–polarized MBCs in allergy. Initiation of a recall response in the absence of IL-4 and IL-13 signaling diminished the type 2 MBC phenotype in mice and humans. This permitted the emergence of long-lived Ag-specific IgG2c+ MBCs in mice. The divergence to a type 1–like response was dependent on interferon-γ signaling and arose from both unswitched and class-switched Ag-specific B cells in vivo. This reprogrammed fate was sustained even beyond therapeutic intervention, revealing fundamental insights into the plasticity of the allergen-specific recall response.
{"title":"Pathogenic IgE-fated memory B cell responses retain functional plasticity","authors":"Kelly Bruton, Allyssa Phelps, Atai Ariaz, Allison Fang, Tina D. Walker, Jianping Wen, Sharon S. Khavkine-Binstock, Danielle Della Libera, Olivia Mann-Delany, Niels Peter H. Knudsen, Siyon Gadkar, Emily Grydziuszko, Joshua F. E. Koenig, Aidan Gagnon, Susan Waserman, Peter S. Andersen, Manel Jordana","doi":"10.1126/sciimmunol.ady2268","DOIUrl":"10.1126/sciimmunol.ady2268","url":null,"abstract":"<div >Long-lived immunoglobulin E (IgE) responses against innocuous environmental and dietary antigens (Ags) are maintained by an IgG1-dominant memory B cell (MBC) compartment primed for interleukin-4 (IL-4) responsiveness. The plasticity of the MBC compartment destined for IgE class switch recombination remains poorly understood. In this work, we report critical IL-4 and IL-13 dependency for the pathogenic IgE fate of type 2–polarized MBCs in allergy. Initiation of a recall response in the absence of IL-4 and IL-13 signaling diminished the type 2 MBC phenotype in mice and humans. This permitted the emergence of long-lived Ag-specific IgG2c<sup>+</sup> MBCs in mice. The divergence to a type 1–like response was dependent on interferon-γ signaling and arose from both unswitched and class-switched Ag-specific B cells in vivo. This reprogrammed fate was sustained even beyond therapeutic intervention, revealing fundamental insights into the plasticity of the allergen-specific recall response.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 115","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145888035","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 : 2026-01-02DOI: 10.1126/sciimmunol.adt8858
Vu L. Ngo, Carolin M. Lieber, Hirohito Abo, Michal Kuczma, Jun Zou, Richard K. Plemper, Andrew T. Gewirtz
Respiratory viral infection induces depletion and dysfunction of alveolar macrophages (AMs), resulting in high-susceptibility to life-threatening bacterial pneumonia. Colonization of the intestine by segmented filamentous bacteria (SFB) reprograms AM to resist depletion. Hence, we examined whether SFB protected mice against secondary bacterial infection by Streptococcus pneumoniae, Haemophilus influenzae, or Staphylococcus aureus after influenza A virus (IAV) infection. SFB protected mice against these infections based on pathogen loads and disease symptoms. AM depletion and transplant indicated that SFB-induced AM reprogramming was necessary and sufficient for such protection. Ex vivo analysis revealed that AMs from SFB-colonized mice not only resisted IAV-induced depletion but also were epigenetically reprogrammed to preferentially use oxidative phosphorylation and complement-dependent phagocytosis, which enabled efficient killing of bacteria. AM from SFB-colonized mice held their enhanced antibacterial phenotype even when transplanted into an inflamed interferon-rich post–IAV environment. Thus, gut microbiota composition influences susceptibility to bacterial pneumonia, especially after respiratory viral infection.
{"title":"Segmented filamentous bacteria reprogramming of alveolar macrophages limits postinfluenza bacterial pneumonia","authors":"Vu L. Ngo, Carolin M. Lieber, Hirohito Abo, Michal Kuczma, Jun Zou, Richard K. Plemper, Andrew T. Gewirtz","doi":"10.1126/sciimmunol.adt8858","DOIUrl":"10.1126/sciimmunol.adt8858","url":null,"abstract":"<div >Respiratory viral infection induces depletion and dysfunction of alveolar macrophages (AMs), resulting in high-susceptibility to life-threatening bacterial pneumonia. Colonization of the intestine by segmented filamentous bacteria (SFB) reprograms AM to resist depletion. Hence, we examined whether SFB protected mice against secondary bacterial infection by <i>Streptococcus pneumoniae</i>, <i>Haemophilus influenzae</i>, or <i>Staphylococcus aureus</i> after influenza A virus (IAV) infection. SFB protected mice against these infections based on pathogen loads and disease symptoms. AM depletion and transplant indicated that SFB-induced AM reprogramming was necessary and sufficient for such protection. Ex vivo analysis revealed that AMs from SFB-colonized mice not only resisted IAV-induced depletion but also were epigenetically reprogrammed to preferentially use oxidative phosphorylation and complement-dependent phagocytosis, which enabled efficient killing of bacteria. AM from SFB-colonized mice held their enhanced antibacterial phenotype even when transplanted into an inflamed interferon-rich post–IAV environment. Thus, gut microbiota composition influences susceptibility to bacterial pneumonia, especially after respiratory viral infection.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 115","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145887986","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 : 2026-01-02DOI: 10.1126/sciimmunol.adu4944
Ruijun He, Farid F. Kadyrov, Andrew L. Koenig, Pan Ma, Andrea Bredemeyer, Mandy M. Chan, Joel D. Schilling, Shibali Das, Joseph S. Lagas, Daniel Kreisel, Carla J. Weinheimer, Jessica M. Nigro, Attila Kovacs, Nima Mosammaparast, Kory J. Lavine
Heart failure and ischemic heart disease represent prevalent causes of death among cancer survivors. Despite extensive use of conventional chemotherapies, a limited understanding of how these agents affect the cardiac immune landscape exists. Using mouse models, we show that DNA-damaging agents selectively deplete cardiac-resident macrophages through activation of p53 signaling and resultant necroptosis and apoptosis. Genetic lineage tracing, transcriptomic profiling, and functional studies revealed that recruited monocytes progressively reconstitute the cardiac-resident macrophage compartment, were transcriptionally distinct from embryonic-derived cardiac-resident macrophages, and conferred protection from subsequent hypertensive and ischemic cardiac injury in mice. Monocyte-derived resident-like cardiac macrophages suppressed inflammation and attenuated adverse myocardial remodeling through a type I interferon–dependent mechanism. Collectively, these findings highlight unrecognized effects of DNA-damaging chemotherapies on the cardiac immune landscape and shed light on our understanding of monocyte plasticity and resident macrophage dynamics.
{"title":"DNA-damaging chemotherapy reshapes cardiac-resident macrophage composition and function","authors":"Ruijun He, Farid F. Kadyrov, Andrew L. Koenig, Pan Ma, Andrea Bredemeyer, Mandy M. Chan, Joel D. Schilling, Shibali Das, Joseph S. Lagas, Daniel Kreisel, Carla J. Weinheimer, Jessica M. Nigro, Attila Kovacs, Nima Mosammaparast, Kory J. Lavine","doi":"10.1126/sciimmunol.adu4944","DOIUrl":"10.1126/sciimmunol.adu4944","url":null,"abstract":"<div >Heart failure and ischemic heart disease represent prevalent causes of death among cancer survivors. Despite extensive use of conventional chemotherapies, a limited understanding of how these agents affect the cardiac immune landscape exists. Using mouse models, we show that DNA-damaging agents selectively deplete cardiac-resident macrophages through activation of p53 signaling and resultant necroptosis and apoptosis. Genetic lineage tracing, transcriptomic profiling, and functional studies revealed that recruited monocytes progressively reconstitute the cardiac-resident macrophage compartment, were transcriptionally distinct from embryonic-derived cardiac-resident macrophages, and conferred protection from subsequent hypertensive and ischemic cardiac injury in mice. Monocyte-derived resident-like cardiac macrophages suppressed inflammation and attenuated adverse myocardial remodeling through a type I interferon–dependent mechanism. Collectively, these findings highlight unrecognized effects of DNA-damaging chemotherapies on the cardiac immune landscape and shed light on our understanding of monocyte plasticity and resident macrophage dynamics.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 115","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145887985","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 : 2025-12-19DOI: 10.1126/sciimmunol.adp8843
Lennard W. Duck, Melissa S. Jennings, Jung-Shan Hsu, Covenant F. Adeboboye, E. Leighann Morgan, Kiarra J. Coger, Barbara J. Klocke, Dave D. Hill, Katie L. Alexander, Alexander F. Rosenberg, Goo Lee, Qing Zhao, Charles O. Elson, Craig L. Maynard
Adaptive immune responses to commensal flagellins are hallmarks of Crohn’s disease (CD), but it is unclear whether flagellins themselves promote inflammation or whether flagellated commensals can also be colitogenic. Here, we show that the arrangement of motility loci and the diversity of encoded flagellins can separate flagellated gut-derived Clostridia into at least two functionally distinct groups. In gnotobiotic mice, both groups induce tolerogenic responses, but only one group promoted tissue inflammation after barrier disruption. Specific flagellins expressed by members of this proinflammatory group displayed a heightened capacity for TLR5 activation that could be modulated by modification of a defined region of the flagellin D0 domain. Bacteria belonging to the proinflammatory group were also found to be elevated in CD biopsies. Together, this study identified key features of specific commensal bacteria that have colitogenic potential and revealed one mechanism whereby these organisms can potentially initiate intestinal inflammation.
{"title":"Divergent immune responses to commensal bacteria bearing distinct motility signatures","authors":"Lennard W. Duck, Melissa S. Jennings, Jung-Shan Hsu, Covenant F. Adeboboye, E. Leighann Morgan, Kiarra J. Coger, Barbara J. Klocke, Dave D. Hill, Katie L. Alexander, Alexander F. Rosenberg, Goo Lee, Qing Zhao, Charles O. Elson, Craig L. Maynard","doi":"10.1126/sciimmunol.adp8843","DOIUrl":"10.1126/sciimmunol.adp8843","url":null,"abstract":"<div >Adaptive immune responses to commensal flagellins are hallmarks of Crohn’s disease (CD), but it is unclear whether flagellins themselves promote inflammation or whether flagellated commensals can also be colitogenic. Here, we show that the arrangement of motility loci and the diversity of encoded flagellins can separate flagellated gut-derived <i>Clostridia</i> into at least two functionally distinct groups. In gnotobiotic mice, both groups induce tolerogenic responses, but only one group promoted tissue inflammation after barrier disruption. Specific flagellins expressed by members of this proinflammatory group displayed a heightened capacity for TLR5 activation that could be modulated by modification of a defined region of the flagellin D0 domain. Bacteria belonging to the proinflammatory group were also found to be elevated in CD biopsies. Together, this study identified key features of specific commensal bacteria that have colitogenic potential and revealed one mechanism whereby these organisms can potentially initiate intestinal inflammation.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 114","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777705","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 : 2025-12-19DOI: 10.1126/sciimmunol.adk0853
Zhi Li, Jing Wang, Juan Du, Jun Li, Yanan Song, Junji Zhu, Ziyi Li, Wei Zhou, Shiyun Chen, Lijie Yang, Maohui Feng, Xiaolian Cai, Katryn J. Stacey, Wuhan Xiao
Processes that control tissue inflammation are essential to restore homeostasis after infection. The transcription factor NF-κB plays a central role in coordinating inflammation, but the mechanisms that regulate NF-κB signaling are not fully understood. Here, we identify OCEL1 (occludin/ELL domain containing 1) as a negative regulator of NF-κB signaling. In the absence of infection, human OCEL1 bound to the LZ domain of NEMO (NF-κB essential modulator) and inhibited TRAF6-mediated K63-linked polyubiquitination, suppressing NF-κB signaling. During infection, OCEL1-mediated negative regulation of NF-κB signaling was impaired by FK506-binding protein bacterial peptidyl-prolyl cis/trans isomerases, which bound to OCEL1 in an amino-terminal palindromic proline–rich element (PPE) and promoted its degradation. Mice expressing a mutant version of the human OCEL1 PPE had dampened inflammation and increased susceptibility to Pseudomonas aeruginosa infection. Thus, the PPE of human OCEL1 senses bacterial infection, and its degradation releases the suppression of NF-κB signaling and promotes inflammation.
{"title":"Human OCEL1 senses bacterial infection to unlock inflammatory responses","authors":"Zhi Li, Jing Wang, Juan Du, Jun Li, Yanan Song, Junji Zhu, Ziyi Li, Wei Zhou, Shiyun Chen, Lijie Yang, Maohui Feng, Xiaolian Cai, Katryn J. Stacey, Wuhan Xiao","doi":"10.1126/sciimmunol.adk0853","DOIUrl":"10.1126/sciimmunol.adk0853","url":null,"abstract":"<div >Processes that control tissue inflammation are essential to restore homeostasis after infection. The transcription factor NF-κB plays a central role in coordinating inflammation, but the mechanisms that regulate NF-κB signaling are not fully understood. Here, we identify <i>OCEL1</i> (<i>occludin/ELL domain containing 1</i>) as a negative regulator of NF-κB signaling. In the absence of infection, human OCEL1 bound to the LZ domain of NEMO (NF-κB essential modulator) and inhibited TRAF6-mediated K63-linked polyubiquitination, suppressing NF-κB signaling. During infection, OCEL1-mediated negative regulation of NF-κB signaling was impaired by FK506-binding protein bacterial peptidyl-prolyl cis/trans isomerases, which bound to OCEL1 in an amino-terminal palindromic proline–rich element (PPE) and promoted its degradation. Mice expressing a mutant version of the human <i>OCEL1</i> PPE had dampened inflammation and increased susceptibility to <i>Pseudomonas aeruginosa</i> infection. Thus, the PPE of human OCEL1 senses bacterial infection, and its degradation releases the suppression of NF-κB signaling and promotes inflammation.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 114","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777706","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 : 2025-12-19DOI: 10.1126/sciimmunol.aeb2657
Luciana P. Tavares, Thayse R. Brüggemann, R. Elaine Cagnina, Robert Nshimiyimana, Ana B. Villaseñor-Altamirano, Rafael M. Rezende, Toby B. Lanser, Xiaoli Liu, Marjorie E. Bateman, Nandini Krishnamoorthy, Stephanie Pons, Melody G. Duvall, Raja-Elie E. Abdulnour, Alexander Tavares, Kathleen J. Haley, Rajesh K. Krishnan, Charles N. Serhan, Bruce D. Levy
Neutrophils have vital proinflammatory protective functions, but gene expression changes in neutrophils found in inflamed tissues suggest additional proresolving effects. We identified a neutrophil subset with a distinct phenotype and function that emerges in mouse lungs during resolution of injury. These resolution-phase neutrophils increased expression of Siglec-F (sialic acid–binding Ig-like lectin F), Alox15 (12/15-lipoxygenase), and Csf1 (colony-stimulating factor 1). Siglec-F+ neutrophils promoted macrophage differentiation and produced specialized proresolving mediators that accelerated injury resolution. Neutrophil depletion hindered lung epithelial catabatic responses, whereas adoptive transfer of Siglec-F+ neutrophils accelerated restitution of lung epithelial cells. Transforming growth factor–β (TGF-β) and granulocyte-macrophage colony-stimulating factor (GM-CSF), acting via activator protein-1 (AP-1)/Jun, promoted expression of Siglec-F in mouse neutrophils and ALOX15 in mouse and human neutrophils. In patients with respiratory failure, ALOX15+ neutrophils were present in the bronchoalveolar lavage samples, and their frequency correlated with improved oxygenation. Thus, Siglec-F+ ALOX15+ proresolving neutrophils contribute to tissue injury responses.
中性粒细胞具有重要的促炎保护功能，但在炎症组织中发现的中性粒细胞的基因表达变化提示了额外的促炎作用。我们确定了一个具有独特表型和功能的中性粒细胞亚群，在损伤消退期间出现在小鼠肺中。这些溶解期中性粒细胞增加了Siglec-F（唾液酸结合igg样凝集素F）、Alox15（12/15-脂氧合酶）和Csf1（集落刺激因子1）的表达。Siglec-F +中性粒细胞促进巨噬细胞分化并产生专门的促进介质，加速损伤消退。中性粒细胞耗竭阻碍了肺上皮细胞的消退反应，而过继性转移siglece - f +中性粒细胞则加速了肺上皮细胞的恢复。转化生长因子-β (TGF-β)和粒细胞-巨噬细胞集落刺激因子（GM-CSF）通过激活蛋白-1 (AP-1)/Jun作用，促进小鼠中性粒细胞中siglece - f的表达，促进小鼠和人中性粒细胞中ALOX15的表达。在呼吸衰竭患者中，支气管肺泡灌洗液样本中存在ALOX15 +中性粒细胞，其频率与氧合改善相关。因此，siglece - f + ALOX15 +促中性粒细胞参与组织损伤反应。
{"title":"Siglec-F+ neutrophils promote the resolution of acute lung injury through ALOX15 induction","authors":"Luciana P. Tavares, Thayse R. Brüggemann, R. Elaine Cagnina, Robert Nshimiyimana, Ana B. Villaseñor-Altamirano, Rafael M. Rezende, Toby B. Lanser, Xiaoli Liu, Marjorie E. Bateman, Nandini Krishnamoorthy, Stephanie Pons, Melody G. Duvall, Raja-Elie E. Abdulnour, Alexander Tavares, Kathleen J. Haley, Rajesh K. Krishnan, Charles N. Serhan, Bruce D. Levy","doi":"10.1126/sciimmunol.aeb2657","DOIUrl":"10.1126/sciimmunol.aeb2657","url":null,"abstract":"<div >Neutrophils have vital proinflammatory protective functions, but gene expression changes in neutrophils found in inflamed tissues suggest additional proresolving effects. We identified a neutrophil subset with a distinct phenotype and function that emerges in mouse lungs during resolution of injury. These resolution-phase neutrophils increased expression of Siglec-F (sialic acid–binding Ig-like lectin F), <i>Alox15</i> (12/15-lipoxygenase), and <i>Csf1</i> (<i>colony-stimulating factor 1</i>). Siglec-F<sup>+</sup> neutrophils promoted macrophage differentiation and produced specialized proresolving mediators that accelerated injury resolution. Neutrophil depletion hindered lung epithelial catabatic responses, whereas adoptive transfer of Siglec-F<sup>+</sup> neutrophils accelerated restitution of lung epithelial cells. Transforming growth factor–β (TGF-β) and granulocyte-macrophage colony-stimulating factor (GM-CSF), acting via activator protein-1 (AP-1)/Jun, promoted expression of Siglec-F in mouse neutrophils and ALOX15 in mouse and human neutrophils. In patients with respiratory failure, ALOX15<sup>+</sup> neutrophils were present in the bronchoalveolar lavage samples, and their frequency correlated with improved oxygenation. Thus, Siglec-F<sup>+</sup> ALOX15<sup>+</sup> proresolving neutrophils contribute to tissue injury responses.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 114","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777703","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 : 2025-12-19DOI: 10.1126/sciimmunol.adz2294
Bin-Jin Hwang, Erika J. Crosby, David T. Severson, Timothy N. Trotter, Jason McBane, Li-Chung Tsao, Tao Wang, Cong-Xiao Liu, Xiao-Yi Yang, Gangjun Lei, Junping Wei, Xingru Ma, Bushanqing Liu, Amy Hobeika, Michael Morse, Jesuchristopher Joseph, Ethan Agritelley, Elishama Kanu, Karrie Comatas, Tibor Keler, Li-Zhen He, Herbert Kim Lyerly, Zachary C. Hartman
Tumor antigen vaccination represents an appealing approach for cancer but has failed to materialize as oncologic standard of care. To understand long-term vaccine efficacy, we conducted a retrospective analysis of patients with human epidermal growth receptor 2+ (HER2+) breast cancer who received HER2-targeting vaccines and survived for >18 years. PBMC analysis revealed HER2-specific CD27+ memory CD4 and CD8 T cells, suggesting that CD27 signaling supports long-term immune memory. In human CD27 transgenic mice, combining HER2 vaccination with anti-CD27 agonism enhanced HER2-specific responses, particularly long-lived CD4 memory T cells. Murine models demonstrated ~40% tumor regression with combined therapy compared with vaccine alone (~6%). Additional scRNA-seq analysis identified CD4 T cells with a distinct gene expression profile, and depletion/adoptive transfer studies validated that CD4 T cells were essential for this effect. These findings suggest that CD27 agonism enhances vaccine-induced antigen-specific CD4 T cell responses, enabling durable antitumor immunity not entirely dependent on CD8 T cells.
{"title":"CD27 agonism enhances long-lived CD4 T cell vaccine responses critical for antitumor immunity","authors":"Bin-Jin Hwang, Erika J. Crosby, David T. Severson, Timothy N. Trotter, Jason McBane, Li-Chung Tsao, Tao Wang, Cong-Xiao Liu, Xiao-Yi Yang, Gangjun Lei, Junping Wei, Xingru Ma, Bushanqing Liu, Amy Hobeika, Michael Morse, Jesuchristopher Joseph, Ethan Agritelley, Elishama Kanu, Karrie Comatas, Tibor Keler, Li-Zhen He, Herbert Kim Lyerly, Zachary C. Hartman","doi":"10.1126/sciimmunol.adz2294","DOIUrl":"10.1126/sciimmunol.adz2294","url":null,"abstract":"<div >Tumor antigen vaccination represents an appealing approach for cancer but has failed to materialize as oncologic standard of care. To understand long-term vaccine efficacy, we conducted a retrospective analysis of patients with human epidermal growth receptor 2<sup>+</sup> (HER2<sup>+</sup>) breast cancer who received HER2-targeting vaccines and survived for >18 years. PBMC analysis revealed HER2-specific CD27<sup>+</sup> memory CD4 and CD8 T cells, suggesting that CD27 signaling supports long-term immune memory. In human CD27 transgenic mice, combining HER2 vaccination with anti-CD27 agonism enhanced HER2-specific responses, particularly long-lived CD4 memory T cells. Murine models demonstrated ~40% tumor regression with combined therapy compared with vaccine alone (~6%). Additional scRNA-seq analysis identified CD4 T cells with a distinct gene expression profile, and depletion/adoptive transfer studies validated that CD4 T cells were essential for this effect. These findings suggest that CD27 agonism enhances vaccine-induced antigen-specific CD4 T cell responses, enabling durable antitumor immunity not entirely dependent on CD8 T cells.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 114","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777704","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 : 2025-12-12DOI: 10.1126/sciimmunol.adn2093
Rúben G. R. Pinheiro, Bruno Silva-Santos
γδ T cells are promising players in immunotherapy because of pleiotropic functions, many of which can be preprogrammed in the thymus. Here, we review the cellular and molecular mechanisms that underlie γδ T cell development in the mouse and human thymi, focusing on their acquisition of diverse cytotoxic or cytokine-secreting functions and their dependence on interactions with the specialized thymic epithelium. We discuss the most recent findings and models that inform our understanding of γδ T cell differentiation and may affect the development of γδ T cell–based immunotherapies.
{"title":"Reaching maturity: Thymic γδ T cell differentiation in mice and humans","authors":"Rúben G. R. Pinheiro, Bruno Silva-Santos","doi":"10.1126/sciimmunol.adn2093","DOIUrl":"10.1126/sciimmunol.adn2093","url":null,"abstract":"<div >γδ T cells are promising players in immunotherapy because of pleiotropic functions, many of which can be preprogrammed in the thymus. Here, we review the cellular and molecular mechanisms that underlie γδ T cell development in the mouse and human thymi, focusing on their acquisition of diverse cytotoxic or cytokine-secreting functions and their dependence on interactions with the specialized thymic epithelium. We discuss the most recent findings and models that inform our understanding of γδ T cell differentiation and may affect the development of γδ T cell–based immunotherapies.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 114","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728774","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 : 2025-12-12DOI: 10.1126/sciimmunol.adz8650
Thomas M. Fenton, Line Wulff, Venla Väänänen, Gareth-Rhys Jones, Camilla Koldbæk Lemvigh, Lene B. Riis, Mads Damsgaard Wewer, Julien Vandamme, Peter B. Jørgensen, Calum C. Bain, Kirstine G. Belling, Gwo-Tzer Ho, Tune H. Pers, Anja Poulsen, Gorm R. Madsen, Ole H. Nielsen, Henrik L. Jakobsen, Jose MG. Izarzugaza, Flemming Bendtsen, Søren Brunak, Allan M. Mowat, Lars R. Olsen, Urs Mörbe, William W. Agace
Understanding of mononuclear phagocyte (MNP) diversity in the human intestine and the alterations this compartment undergoes in inflammation remains incomplete. Here, we used single-cell RNA sequencing, cellular indexing of trancriptomes and epitopes by sequencing, flow cytometry, and imaging to explore MNP heterogeneity in human ileal and colonic laminae propriae (LPs) in health and Crohn’s disease (CD). In addition to monocytes, macrophage subsets, and conventional type 1 dendritic cells (cDC1s) and cDC2s, we found a CD1c+ cDC subset with transcriptional features of DC3s. Using computational tools, we identified monocyte-to-macrophage trajectories as well as putative subset–specific DC precursors. We further showed that LP CCR7+ cDCs are increased in CD and provided evidence that these cells arise from intestinal cDC2s/DC3s but not cDC1s. Collectively, these findings extend our current understanding of intestinal MNP diversity and development, highlighting both tissue-specific and inflammation-induced changes in MNP composition and function.
{"title":"Heterogeneity of the intestinal mononuclear phagocyte compartment in health and inflammatory bowel disease","authors":"Thomas M. Fenton, Line Wulff, Venla Väänänen, Gareth-Rhys Jones, Camilla Koldbæk Lemvigh, Lene B. Riis, Mads Damsgaard Wewer, Julien Vandamme, Peter B. Jørgensen, Calum C. Bain, Kirstine G. Belling, Gwo-Tzer Ho, Tune H. Pers, Anja Poulsen, Gorm R. Madsen, Ole H. Nielsen, Henrik L. Jakobsen, Jose MG. Izarzugaza, Flemming Bendtsen, Søren Brunak, Allan M. Mowat, Lars R. Olsen, Urs Mörbe, William W. Agace","doi":"10.1126/sciimmunol.adz8650","DOIUrl":"10.1126/sciimmunol.adz8650","url":null,"abstract":"<div >Understanding of mononuclear phagocyte (MNP) diversity in the human intestine and the alterations this compartment undergoes in inflammation remains incomplete. Here, we used single-cell RNA sequencing, cellular indexing of trancriptomes and epitopes by sequencing, flow cytometry, and imaging to explore MNP heterogeneity in human ileal and colonic laminae propriae (LPs) in health and Crohn’s disease (CD). In addition to monocytes, macrophage subsets, and conventional type 1 dendritic cells (cDC1s) and cDC2s, we found a CD1c<sup>+</sup> cDC subset with transcriptional features of DC3s. Using computational tools, we identified monocyte-to-macrophage trajectories as well as putative subset–specific DC precursors. We further showed that LP <i>CCR7</i><sup>+</sup> cDCs are increased in CD and provided evidence that these cells arise from intestinal cDC2s/DC3s but not cDC1s. Collectively, these findings extend our current understanding of intestinal MNP diversity and development, highlighting both tissue-specific and inflammation-induced changes in MNP composition and function.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 114","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728775","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 : 2025-12-12DOI: 10.1126/sciimmunol.adz2273
Tian-Gen Chang, Jay Friedman, Paul E. Clavijo, Yvette Robbins, Marco Craveiro, Angel Huynh, Mohd Saleem Dar, Xinping Yang, Yingying Cao, Cem M. Sievers, Christopher Silvin, Christian Samaniego Davila, Michael C. Kelly, James W. Hodge, Nancy P. Judd, Wojciech K. Mydlarz, Vassiliki Saloura, Alejandro A. Schäffer, Eytan Ruppin, Clint T. Allen
Neutrophils frequently adopt immunosuppressive phenotypes in tumors, yet the underlying mechanisms remain incompletely understood. Here, we identify the transcription factor early growth response protein 1 (EGR1) as a key regulator of nuclear morphology and immunosuppressive function in tumor-associated neutrophils. Hypoxia-induced EGR1 expression in neutrophils led to altered nuclear morphology and up-regulation of immunosuppressive factors and T cell suppression capacity. Neutrophils from Egr1-deficient mice failed to undergo these hypoxia-driven pathological changes. Adoptive transfer of wild-type neutrophils into a neutrophil-deficient mouse model of oral cavity cancer conferred resistance to programmed cell death 1 (PD-1) blockade, whereas transfer of Egr1-deficient neutrophils restored sensitivity to immunotherapy. Pharmacologic inhibition of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) pathway suppressed hypoxia-induced Egr1 expression and immunosuppressive capacity in neutrophils while enhancing PD-1 blockade–associated tumor control. An EGR1+ neutrophil transcriptional signature predicted poor clinical outcomes across multiple cancer types. These findings identify EGR1 as a hypoxia-inducible driver of neutrophil-mediated immunosuppression and provide a basis for targeting the hypoxia-EGR1 axis to overcome immunotherapy resistance.
{"title":"Hypoxia-induced EGR1 remodels neutrophils to suppress antitumor immunity","authors":"Tian-Gen Chang, Jay Friedman, Paul E. Clavijo, Yvette Robbins, Marco Craveiro, Angel Huynh, Mohd Saleem Dar, Xinping Yang, Yingying Cao, Cem M. Sievers, Christopher Silvin, Christian Samaniego Davila, Michael C. Kelly, James W. Hodge, Nancy P. Judd, Wojciech K. Mydlarz, Vassiliki Saloura, Alejandro A. Schäffer, Eytan Ruppin, Clint T. Allen","doi":"10.1126/sciimmunol.adz2273","DOIUrl":"10.1126/sciimmunol.adz2273","url":null,"abstract":"<div >Neutrophils frequently adopt immunosuppressive phenotypes in tumors, yet the underlying mechanisms remain incompletely understood. Here, we identify the transcription factor early growth response protein 1 (EGR1) as a key regulator of nuclear morphology and immunosuppressive function in tumor-associated neutrophils. Hypoxia-induced <i>EGR1</i> expression in neutrophils led to altered nuclear morphology and up-regulation of immunosuppressive factors and T cell suppression capacity. Neutrophils from <i>Egr1</i>-deficient mice failed to undergo these hypoxia-driven pathological changes. Adoptive transfer of wild-type neutrophils into a neutrophil-deficient mouse model of oral cavity cancer conferred resistance to programmed cell death 1 (PD-1) blockade, whereas transfer of <i>Egr1</i>-deficient neutrophils restored sensitivity to immunotherapy. Pharmacologic inhibition of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK) pathway suppressed hypoxia-induced <i>Egr1</i> expression and immunosuppressive capacity in neutrophils while enhancing PD-1 blockade–associated tumor control. An <i>EGR1</i><sup>+</sup> neutrophil transcriptional signature predicted poor clinical outcomes across multiple cancer types. These findings identify EGR1 as a hypoxia-inducible driver of neutrophil-mediated immunosuppression and provide a basis for targeting the hypoxia-EGR1 axis to overcome immunotherapy resistance.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"10 114","pages":""},"PeriodicalIF":16.3,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.science.org/doi/reader/10.1126/sciimmunol.adz2273","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145728776","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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