Pub Date : 2026-01-16DOI: 10.1126/sciimmunol.adz7275
Keling Huang, Xiaoxue Li, Wenhua Liang, Shuyao Wu, Youqiong Ye, Yan Lu, Junke Zheng, Weifang Wang, Qifan Zheng, Guo Fu, Song Gao, Feng Wang
Immune checkpoint blockade (ICB) has transformed cancer treatment, yet its efficacy is often limited by the progressive exhaustion of tumor-reactive CD8 T cells. By analyzing transcriptomes of CD8 T cells from patients treated with ICB across cancer types, we found that prothymosin alpha (PTMA) is highly expressed in progenitor exhausted T (TPEX) cells and is associated with treatment response. PTMA expression was directly controlled by T cell factor 1 (TCF1), a central regulator of TPEX cell maintenance in the tumor microenvironment. In mice, genetic deletion of Ptma from T cells compromised CD8 T cell persistence in tumors and abolished the therapeutic effect of programmed cell death protein 1 (PD-1) blockade. PTMA preserved mitochondrial DNA integrity through interaction with mitochondrial transcription factor A (TFAM), sustaining T cell oxidative phosphorylation under metabolic stress. Our findings identify the TCF1-PTMA axis as a molecular link between mitochondrial fitness and durable T cell–mediated antitumor immunity, offering insights and potential directions for future therapeutic strategies to boost immunotherapy efficacy.
{"title":"PTMA safeguards mitochondrial integrity to sustain metabolic function and antitumor activity of CD8 T cells","authors":"Keling Huang, Xiaoxue Li, Wenhua Liang, Shuyao Wu, Youqiong Ye, Yan Lu, Junke Zheng, Weifang Wang, Qifan Zheng, Guo Fu, Song Gao, Feng Wang","doi":"10.1126/sciimmunol.adz7275","DOIUrl":"10.1126/sciimmunol.adz7275","url":null,"abstract":"<div >Immune checkpoint blockade (ICB) has transformed cancer treatment, yet its efficacy is often limited by the progressive exhaustion of tumor-reactive CD8 T cells. By analyzing transcriptomes of CD8 T cells from patients treated with ICB across cancer types, we found that prothymosin alpha (PTMA) is highly expressed in progenitor exhausted T (T<sub>PEX</sub>) cells and is associated with treatment response. PTMA expression was directly controlled by T cell factor 1 (TCF1), a central regulator of T<sub>PEX</sub> cell maintenance in the tumor microenvironment. In mice, genetic deletion of <i>Ptma</i> from T cells compromised CD8 T cell persistence in tumors and abolished the therapeutic effect of programmed cell death protein 1 (PD-1) blockade. PTMA preserved mitochondrial DNA integrity through interaction with mitochondrial transcription factor A (TFAM), sustaining T cell oxidative phosphorylation under metabolic stress. Our findings identify the TCF1-PTMA axis as a molecular link between mitochondrial fitness and durable T cell–mediated antitumor immunity, offering insights and potential directions for future therapeutic strategies to boost immunotherapy efficacy.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 115","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984124","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 : 2026-01-16DOI: 10.1126/sciimmunol.adr4057
Ming-Ting Tsai, Ryann Callaghan, Charles Ng, Lisette Peres-Tintin, Dean B. Matthews, Nikketa Stanford, Karuna Ganesh, Mary K. Estes, Gretchen E. Diehl
Intestinal macrophages are essential for epithelial barrier repair. In homeostasis, macrophages are continuously replenished by recruitment of circulating C-C chemokine receptor 2 (CCR2)+ monocytes into the intestinal lamina propria (LP), a process that requires the commensal microbiota. The specific microbial factors and downstream host pathways that coordinate macrophage replenishment are inadequately understood. Here, we show that colonization with an Escherichia coli isolate increased CCR2+ macrophages in the intestine and ameliorated pathology in a colitis model. Using human colonic organoids, we report that E. coli colonization induced the secretion of C-C chemokine ligand 2 (CCL2) by intestinal epithelial stem cells, which promoted monocyte migration. Protection in vivo was abolished in the absence of epithelial CCL2. By screening a panel of E. coli, we identified that high flagellin expression correlated with epithelial CCL2 production. Demonstrating a requirement for E. coli flagellin, in vivo protection was lost in mice lacking epithelial Toll-like receptor 5 (TLR5) or after colonization with flagellin-deficient E. coli. Thus, epithelial flagellin sensing by TLR5 recruits CCR2+ macrophages to the intestine, promoting barrier repair.
{"title":"Intestinal epithelial TLR5 signaling promotes barrier-supportive macrophages","authors":"Ming-Ting Tsai, Ryann Callaghan, Charles Ng, Lisette Peres-Tintin, Dean B. Matthews, Nikketa Stanford, Karuna Ganesh, Mary K. Estes, Gretchen E. Diehl","doi":"10.1126/sciimmunol.adr4057","DOIUrl":"10.1126/sciimmunol.adr4057","url":null,"abstract":"<div >Intestinal macrophages are essential for epithelial barrier repair. In homeostasis, macrophages are continuously replenished by recruitment of circulating C-C chemokine receptor 2 (CCR2)<sup>+</sup> monocytes into the intestinal lamina propria (LP), a process that requires the commensal microbiota. The specific microbial factors and downstream host pathways that coordinate macrophage replenishment are inadequately understood. Here, we show that colonization with an <i>Escherichia coli</i> isolate increased CCR2<sup>+</sup> macrophages in the intestine and ameliorated pathology in a colitis model. Using human colonic organoids, we report that <i>E. coli</i> colonization induced the secretion of C-C chemokine ligand 2 (CCL2) by intestinal epithelial stem cells, which promoted monocyte migration. Protection in vivo was abolished in the absence of epithelial CCL2. By screening a panel of <i>E. coli</i>, we identified that high flagellin expression correlated with epithelial CCL2 production. Demonstrating a requirement for <i>E. coli</i> flagellin, in vivo protection was lost in mice lacking epithelial Toll-like receptor 5 (TLR5) or after colonization with flagellin-deficient <i>E. coli</i>. Thus, epithelial flagellin sensing by TLR5 recruits CCR2<sup>+</sup> macrophages to the intestine, promoting barrier repair.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 115","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145984123","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}
The 2′-5′ oligoadenylate synthetases (OASs) are type I interferon–inducible enzymes that, with ribonuclease L (RNase L), have been studied in the context of their coupled action as antiviral effectors. RNase L degrades host and viral ssRNA, affecting diverse cellular processes including translational arrest, interferon response, and apoptosis, all of which are thought to restrict viral replication. Recent studies of recessive inborn errors of human OAS1, OAS2, and RNase L, however, revealed that for SARS-CoV-2 infection, the main protective action of this pathway in natura may be through restricting phagocyte-driven postviral inflammation rather than restricting early viral replication in the respiratory tract. This finding is consistent with the identification of gain-of-function OAS1 mutations in humans with autoinflammation also driven by myeloid cells. Here, we retrace the investigation of the OAS–RNase L pathway, focusing on these recent in natura studies in humans that reposition the pathway as a determinant of the inflammatory response under natural conditions of infection.
{"title":"The OAS–RNase L pathway: Insights from experiments of nature","authors":"Danyel Lee, Krishnamurthy Malathi, Tsubasa Okano, Koji Nakajima, Aurélie Cobat, Tomohiro Morio, Jean-Laurent Casanova, Shen-Ying Zhang","doi":"10.1126/sciimmunol.ads9407","DOIUrl":"10.1126/sciimmunol.ads9407","url":null,"abstract":"<div >The 2′-5′ oligoadenylate synthetases (OASs) are type I interferon–inducible enzymes that, with ribonuclease L (RNase L), have been studied in the context of their coupled action as antiviral effectors. RNase L degrades host and viral ssRNA, affecting diverse cellular processes including translational arrest, interferon response, and apoptosis, all of which are thought to restrict viral replication. Recent studies of recessive inborn errors of human OAS1, OAS2, and RNase L, however, revealed that for SARS-CoV-2 infection, the main protective action of this pathway in natura may be through restricting phagocyte-driven postviral inflammation rather than restricting early viral replication in the respiratory tract. This finding is consistent with the identification of gain-of-function <i>OAS1</i> mutations in humans with autoinflammation also driven by myeloid cells. Here, we retrace the investigation of the OAS–RNase L pathway, focusing on these recent in natura studies in humans that reposition the pathway as a determinant of the inflammatory response under natural conditions of infection.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 115","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937787","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 : 2026-01-09DOI: 10.1126/sciimmunol.aee6626
{"title":"Erratum for the Research Article “T cell receptor–triggered nuclear actin network formation drives CD4+ T cell effector functions” by N. Tsopoulidis et al.","authors":"","doi":"10.1126/sciimmunol.aee6626","DOIUrl":"10.1126/sciimmunol.aee6626","url":null,"abstract":"","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 115","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937786","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 : 2026-01-09DOI: 10.1126/sciimmunol.adw0732
Shota Torigoe, Sumayah Salie, Roanne Keeton, Beren Aylan, Ben J. Appelmelk, David L. Williams, Douglas W. Lowman, Toshihiko Sugiki, Sohkichi Matsumoto, Akira Kawano, Satoru Mizuno, Kazuhiro Matsuo, Jonas N. Søndergaard, James B. Wing, Maxine A. Höft, Romey Shoesmith, Mthawelanga Ndengane, Anna K. Coussens, Janet A. Willment, Maximiliano G. Gutierrez, Jennifer Claire Hoving, Sho Yamasaki, Gordon D. Brown
Mycobacteria have a cell envelope that can act as a shield against host defense. This study shows that mycobacteria survive in host macrophages by targeting the innate host receptor dectin-1 through a noncanonical ligand. Compared with wild-type (WT) mice, dectin-1–deficient mice were more resistant to infection to mycobacteria. Dectin-1–deficient mice presented with substantially reduced bacterial burdens, inflammatory cytokines, and infiltrating myeloid cells, such as neutrophils and macrophages. Intracellular survival of these bacteria was reduced in macrophages derived from dectin-1–deficient mice compared with those from WT mice. Cellular characterization of mycobacteria-infected macrophages indicated that the presence of dectin-1 altered phagosomal maturation and association with markers of autophagy. Activity-based purification and nuclear magnetic resonance spectrometry identified branched α-glucan as the dectin-1 mycobacterial ligand. This branched glucan was essential for activating dectin-1. These results show that mycobacterial α-glucan targets dectin-1 to facilitate intracellular bacterial survival.
{"title":"Mycobacterial α-glucans hijack dectin-1 to facilitate intracellular bacterial survival","authors":"Shota Torigoe, Sumayah Salie, Roanne Keeton, Beren Aylan, Ben J. Appelmelk, David L. Williams, Douglas W. Lowman, Toshihiko Sugiki, Sohkichi Matsumoto, Akira Kawano, Satoru Mizuno, Kazuhiro Matsuo, Jonas N. Søndergaard, James B. Wing, Maxine A. Höft, Romey Shoesmith, Mthawelanga Ndengane, Anna K. Coussens, Janet A. Willment, Maximiliano G. Gutierrez, Jennifer Claire Hoving, Sho Yamasaki, Gordon D. Brown","doi":"10.1126/sciimmunol.adw0732","DOIUrl":"10.1126/sciimmunol.adw0732","url":null,"abstract":"<div >Mycobacteria have a cell envelope that can act as a shield against host defense. This study shows that mycobacteria survive in host macrophages by targeting the innate host receptor dectin-1 through a noncanonical ligand. Compared with wild-type (WT) mice, dectin-1–deficient mice were more resistant to infection to mycobacteria. Dectin-1–deficient mice presented with substantially reduced bacterial burdens, inflammatory cytokines, and infiltrating myeloid cells, such as neutrophils and macrophages. Intracellular survival of these bacteria was reduced in macrophages derived from dectin-1–deficient mice compared with those from WT mice. Cellular characterization of mycobacteria-infected macrophages indicated that the presence of dectin-1 altered phagosomal maturation and association with markers of autophagy. Activity-based purification and nuclear magnetic resonance spectrometry identified branched α-glucan as the dectin-1 mycobacterial ligand. This branched glucan was essential for activating dectin-1. These results show that mycobacterial α-glucan targets dectin-1 to facilitate intracellular bacterial survival.</div>","PeriodicalId":21734,"journal":{"name":"Science Immunology","volume":"11 115","pages":""},"PeriodicalIF":16.3,"publicationDate":"2026-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145937788","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.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}
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